Pub Date : 2024-06-26DOI: 10.1007/s00395-024-01064-y
Dominika Lukovic, Mariann Gyöngyösi, Imre J Pavo, Julia Mester-Tonczar, Patrick Einzinger, Katrin Zlabinger, Nina Kastner, Andreas Spannbauer, Denise Traxler, Noemi Pavo, Georg Goliasch, Dietmar Pils, Andras Jakab, Zsuzsanna Szankai, Ina Michel-Behnke, Lu Zhang, Yvan Devaux, Senta Graf, Dietrich Beitzke, Johannes Winkler
Combined [18F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [18F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI.
{"title":"Increased [<sup>18</sup>F]FDG uptake in the infarcted myocardial area displayed by combined PET/CMR correlates with snRNA-seq-detected inflammatory cell invasion.","authors":"Dominika Lukovic, Mariann Gyöngyösi, Imre J Pavo, Julia Mester-Tonczar, Patrick Einzinger, Katrin Zlabinger, Nina Kastner, Andreas Spannbauer, Denise Traxler, Noemi Pavo, Georg Goliasch, Dietmar Pils, Andras Jakab, Zsuzsanna Szankai, Ina Michel-Behnke, Lu Zhang, Yvan Devaux, Senta Graf, Dietrich Beitzke, Johannes Winkler","doi":"10.1007/s00395-024-01064-y","DOIUrl":"https://doi.org/10.1007/s00395-024-01064-y","url":null,"abstract":"<p><p>Combined [<sup>18</sup>F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [<sup>18</sup>F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":7.5,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1007/s00395-024-01058-w
Guangze Zhao, Huifang M Zhang, Ali Reza Nasseri, Fione Yip, Nikita Telkar, Yankuan T Chen, Sana Aghakeshmiri, Christoph Küper, Wan Lam, Wenli Yang, James Zhao, Honglin Luo, Bruce M McManus, Decheng Yang
Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.
{"title":"Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis.","authors":"Guangze Zhao, Huifang M Zhang, Ali Reza Nasseri, Fione Yip, Nikita Telkar, Yankuan T Chen, Sana Aghakeshmiri, Christoph Küper, Wan Lam, Wenli Yang, James Zhao, Honglin Luo, Bruce M McManus, Decheng Yang","doi":"10.1007/s00395-024-01058-w","DOIUrl":"https://doi.org/10.1007/s00395-024-01058-w","url":null,"abstract":"<p><p>Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-18DOI: 10.1007/s00395-024-01040-6
Sally Badawi, Clémence Leboullenger, Matthieu Chourrout, Yves Gouriou, Alexandre Paccalet, Bruno Pillot, Lionel Augeul, Radu Bolbos, Antonino Bongiovani, Nathan Mewton, Thomas Bochaton, Michel Ovize, Meryem Tardivel, Mazen Kurdi, Emmanuelle Canet-Soulas, Claire Crola Da Silva, Gabriel Bidaux
Myocardial infarction (MI) is a serious acute cardiovascular syndrome that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been an early subject of attention in the food industry, specifically for meat consumers. However, rarely if ever have the myoglobin optical properties been used to measure the severity of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the cleared myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it is partly composed by fluorescence of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 h post-reperfusion and decreases with cardioprotection. The infarct size assessed by oxidation-reduction imaging at 3 h post-reperfusion was correlated to the one estimated with late gadolinium enhancement MRI at 24 h post-reperfusion. In conclusion, this original work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.
{"title":"Oxidation-reduction imaging of myoglobin reveals two-phase oxidation in the reperfused myocardium.","authors":"Sally Badawi, Clémence Leboullenger, Matthieu Chourrout, Yves Gouriou, Alexandre Paccalet, Bruno Pillot, Lionel Augeul, Radu Bolbos, Antonino Bongiovani, Nathan Mewton, Thomas Bochaton, Michel Ovize, Meryem Tardivel, Mazen Kurdi, Emmanuelle Canet-Soulas, Claire Crola Da Silva, Gabriel Bidaux","doi":"10.1007/s00395-024-01040-6","DOIUrl":"10.1007/s00395-024-01040-6","url":null,"abstract":"<p><p>Myocardial infarction (MI) is a serious acute cardiovascular syndrome that causes myocardial injury due to blood flow obstruction to a specific myocardial area. Under ischemic-reperfusion settings, a burst of reactive oxygen species is generated, leading to redox imbalance that could be attributed to several molecules, including myoglobin. Myoglobin is dynamic and exhibits various oxidation-reduction states that have been an early subject of attention in the food industry, specifically for meat consumers. However, rarely if ever have the myoglobin optical properties been used to measure the severity of MI. In the current study, we develop a novel imaging pipeline that integrates tissue clearing, confocal and light sheet fluorescence microscopy, combined with imaging analysis, and processing tools to investigate and characterize the oxidation-reduction states of myoglobin in the ischemic area of the cleared myocardium post-MI. Using spectral imaging, we have characterized the endogenous fluorescence of the myocardium and demonstrated that it is partly composed by fluorescence of myoglobin. Under ischemia-reperfusion experimental settings, we report that the infarcted myocardium spectral signature is similar to that of oxidized myoglobin signal that peaks 3 h post-reperfusion and decreases with cardioprotection. The infarct size assessed by oxidation-reduction imaging at 3 h post-reperfusion was correlated to the one estimated with late gadolinium enhancement MRI at 24 h post-reperfusion. In conclusion, this original work suggests that the redox state of myoglobin can be used as a promising imaging biomarker for characterizing and estimating the size of the MI during early phases of reperfusion.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-22DOI: 10.1007/s00395-024-01043-3
Juliette Bréhat, Shirin Leick, Julien Musman, Jin Bo Su, Nicolas Eychenne, Frank Giton, Michael Rivard, Louis-Antoine Barel, Chiara Tropeano, Frederica Vitarelli, Claudio Caccia, Valerio Leoni, Bijan Ghaleh, Sandrine Pons, Didier Morin
Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia-reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia-reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4'-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia-reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia-reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4'-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia-reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4'-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia-reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.
高胆固醇血症是冠状动脉疾病和心脏缺血性事件的主要风险因素。胆固醇本身也会对心肌产生负面影响,与高胆固醇血症无关。此前,我们曾报道心肌缺血再灌注会诱导线粒体胆固醇和氧杂醇的有害积累,而高胆固醇血症会增强这种积累,转运体蛋白(TSPO)配体则会阻止这种积累。在这里,我们研究了固醇在心脏线粒体中积聚并促进线粒体功能障碍的机制。我们对大鼠进行了心肌缺血再灌注,以评估线粒体功能、TSPO 和类固醇生成急性调节蛋白(STAR)水平以及相关的线粒体固醇浓度。用胆固醇合成抑制剂普伐他汀或 TSPO 配体 4'-chlorodiazepam 处理大鼠。我们使用了Tspo基因缺失的大鼠,并对其进行了表型鉴定。抑制胆固醇合成可减少线粒体固醇的积累,并在心肌缺血再灌注过程中保护线粒体。我们发现,心脏线粒体固醇积聚是胆固醇流入量增加的结果,而不是缺血再灌注期间线粒体代谢受到抑制的结果。再灌注时线粒体胆固醇的积累与线粒体 STAR 的增加有关,但与 TSPO 水平的变化无关。4'-氯地西泮抑制了这一机制,并防止了线粒体固醇积累和线粒体缺血再灌注损伤,这是 STAR 和 TSPO 密切合作的基础。相反,Tspo 基因缺失不会改变心脏表型,但却能消除 4'-chlorodiazepam 的作用。本研究揭示了 TSPO 和 STAR 在心肌缺血再灌注过程中促进胆固醇和有害固醇线粒体积累的新型线粒体相互作用。这种相互作用可调节线粒体的平衡,并在线粒体损伤过程中发挥关键作用。
{"title":"Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia-reperfusion: role of TSPO and STAR.","authors":"Juliette Bréhat, Shirin Leick, Julien Musman, Jin Bo Su, Nicolas Eychenne, Frank Giton, Michael Rivard, Louis-Antoine Barel, Chiara Tropeano, Frederica Vitarelli, Claudio Caccia, Valerio Leoni, Bijan Ghaleh, Sandrine Pons, Didier Morin","doi":"10.1007/s00395-024-01043-3","DOIUrl":"10.1007/s00395-024-01043-3","url":null,"abstract":"<p><p>Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia-reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia-reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4'-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia-reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia-reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4'-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia-reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4'-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia-reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-25DOI: 10.1007/s00395-024-01042-4
Y Xiao, Q Wang, H Zhang, R Nederlof, D Bakker, B A Siadari, M W Wesselink, B Preckel, N C Weber, M W Hollmann, B V Schomakers, M van Weeghel, C J Zuurbier
Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.
烟酰胺腺嘌呤二核苷酸(NAD+)水平降低会导致各种病症,如衰老、糖尿病、心力衰竭和缺血再灌注损伤(IRI)。尼古丁酰胺核糖苷(NR)能有效提高 NAD+,因此已成为一种有前途的 NAD+前体治疗剂,最近的研究表明,它是唯一一种能在临床相关麻醉模型中降低心脏 IRI 的药物。然而,NR 是通过哪种代谢途径介导 IRI 保护作用的仍是未知数。此外,胰岛素是已知的心脏保护功效调节剂,但它对 NR 保护作用的影响尚未得到研究。在此,我们使用离体小鼠心脏进行心脏代谢控制,以研究:(1) NR 是否能保护离体心脏免受 IRI 伤害;(2) NR 介导保护的代谢途径;(3) 胰岛素是否会削弱 NR 的保护作用。利用代谢组学确定代谢中间产物的变化,并利用 13C 葡萄糖通量组学确定代谢途径的活性(糖酵解、磷酸戊糖途径(PPP)和线粒体/三羧酸循环(TCA 循环)活性),研究了 NR 对心脏 IRI 的保护作用以及对代谢途径的影响、对灌注(a)葡萄糖+脂肪酸(FA)("轻度糖酵解组")、(b)乳酸+丙酮酸+FA("无糖酵解组")或(c)葡萄糖+FA+胰岛素("高糖酵解组")的离体 C57BL/6N 小鼠心脏进行了检测。在所有三个代谢组中,NR 都能增加心脏的 NAD+。在葡萄糖+FA灌注的心脏中,NR减轻了红外损伤,增加了糖酵解中间体磷酸烯醇丙酮酸(PEP)、TCA中间体琥珀酸和PPP中间体核糖-5P(R5P)/色酮糖-7P(S7P),并与激活的糖酵解有关,而TCA循环或PPP活性没有变化。在 "无糖酵解 "心脏中,NR 失去了保护作用,而 NR 仍会增加 S7P。在胰岛素心脏中,糖酵解在很大程度上被加速,NR 保护失效。NR 仍增加了 PPP 中间产物,现在 S7P 的 13C 标记很高,但 NR 无法增加代谢途径的活动,包括糖酵解。NR对IRI的保护作用只存在于糖酵解较低的心脏中,并且与糖酵解的激活有关。当通过检查 "无糖酵解 "心脏或 "高糖酵解 "心脏来阻止糖酵解的激活时,NR 的保护作用就会消失。这些数据表明,NR 的急性心脏保护作用是通过激活糖酵解介导的,在有胰岛素存在的情况下,由于糖酵解已经升高,NR 的保护作用就会消失。
{"title":"Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside.","authors":"Y Xiao, Q Wang, H Zhang, R Nederlof, D Bakker, B A Siadari, M W Wesselink, B Preckel, N C Weber, M W Hollmann, B V Schomakers, M van Weeghel, C J Zuurbier","doi":"10.1007/s00395-024-01042-4","DOIUrl":"10.1007/s00395-024-01042-4","url":null,"abstract":"<p><p>Decreased nicotinamide adenine dinucleotide (NAD<sup>+</sup>) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD<sup>+</sup> precursor due to efficient NAD<sup>+</sup> elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and <sup>13</sup>C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) (\"mild glycolysis group\"), (b) lactate + pyruvate + FA (\"no glycolysis group\"), or (c) glucose + FA + insulin (\"high glycolysis group\"). NR increased cardiac NAD<sup>+</sup> in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the \"no glycolysis\" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high <sup>13</sup>C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining \"no glycolysis\" hearts or \"high glycolysis\" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-27DOI: 10.1007/s00395-024-01041-5
Inés García-Lunar, Inmaculada Jorge, Jorge Sáiz, Núria Solanes, Ana Paula Dantas, Juan José Rodríguez-Arias, María Ascaso, Carlos Galán-Arriola, Francisco Rafael Jiménez, Elena Sandoval, Jorge Nuche, Maria Moran-Garrido, Emilio Camafeita, Montserrat Rigol, Javier Sánchez-Gonzalez, Valentín Fuster, Jesús Vázquez, Coral Barbas, Borja Ibáñez, Daniel Pereda, Ana García-Álvarez
Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.
{"title":"Metabolic changes contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload: an integrative imaging and omics investigation.","authors":"Inés García-Lunar, Inmaculada Jorge, Jorge Sáiz, Núria Solanes, Ana Paula Dantas, Juan José Rodríguez-Arias, María Ascaso, Carlos Galán-Arriola, Francisco Rafael Jiménez, Elena Sandoval, Jorge Nuche, Maria Moran-Garrido, Emilio Camafeita, Montserrat Rigol, Javier Sánchez-Gonzalez, Valentín Fuster, Jesús Vázquez, Coral Barbas, Borja Ibáñez, Daniel Pereda, Ana García-Álvarez","doi":"10.1007/s00395-024-01041-5","DOIUrl":"10.1007/s00395-024-01041-5","url":null,"abstract":"<p><p>Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11143050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-30DOI: 10.1007/s00395-024-01057-x
David Köhler, Veronika Leiss, Lukas Beichert, Simon Killinger, Daniela Grothe, Ragini Kushwaha, Agnes Schröter, Anna Roslan, Claudia Eggstein, Jule Focken, Tiago Granja, Vasudharani Devanathan, Birgit Schittek, Robert Lukowski, Bettina Weigelin, Peter Rosenberger, Bernd Nürnberg, Sandra Beer-Hammer
Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gαi proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gαi2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gαi2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2-/- → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gαi2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2-/- vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gαi2 for mIRI. Here, we show that infarct size was substantially reduced when Gαi2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2fl/fl LysM-Cre+/tg vs 42.0% Gnai2fl/fl; p < 0.01) or selectively blocked with specific antibodies directed against Gαi2 (AAR: 19.0% (anti-Gαi2) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2fl/fl; LysM-Cre+/tg) vs 31 (Gnai2fl/fl); p < 0.001) and in anti-Gαi2 antibody-treated (PNCs: 9 (anti-Gαi2) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gαi2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gαi2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gαi2) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gαi2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.
中性粒细胞不仅参与抗感染的免疫防御,而且也会加剧缺血和再灌注后的组织损伤。我们之前已经证明,在小鼠体内对调节性 Gαi 蛋白进行基因消减对心肌缺血再灌注损伤(mIRI)既有保护作用,也有有害作用,这取决于删除的是哪一种同工酶。为了更深入、更详细地分析这些发现,我们首先在骨髓嵌合体中研究了驻留心脏细胞和循环血细胞中的 Gαi2 蛋白对 mIRI 的贡献。事实上,所有血细胞中 Gαi2 的缺失都会降低 mIRI 的程度(Gnai2-/- → wt vs 44.0% wt → wt,危险区(AAR)梗死面积的 22.9%;p i2),而非造血细胞中 Gαi2 的缺失则会增加梗死损伤(66.5% wt → Gnai2-/- vs 44.0% wt → wt,mIRI 的 p i2)。在这里,我们发现当使用 LysM 驱动的 Cre 重组酶基因消减中性粒细胞/巨噬细胞中的 Gαi2 信号时,梗死面积会大幅缩小(AAR:17.9% Gnai2fl/fl LysM-Cre+/tg vs 42.0% Gnai2fl/fl; p i2 (AAR:19.0% (anti-Gαi2) vs 49.0% (IgG);p fl/fl;LysM-Cre+/tg) vs 31 (Gnai2fl/fl);p i2 抗体处理(PNCs:9 (anti-Gαi2) vs 33 (IgG);p i2 在血管再灌注前立即进行抗体挑战,不会影响出血时间、心率或中性粒细胞的细胞分布。最后,抗 Gαi2 抗体治疗还能抑制人类中性粒细胞的跨内皮迁移(25 885 个(IgG)对 13 225 个(抗 Gαi2 )中性粒细胞;心肌梗塞患者溶栓和再灌注期间的 p i2 抑制作用应进一步考虑。
{"title":"Targeting Gα<sub>i2</sub> in neutrophils protects from myocardial ischemia reperfusion injury.","authors":"David Köhler, Veronika Leiss, Lukas Beichert, Simon Killinger, Daniela Grothe, Ragini Kushwaha, Agnes Schröter, Anna Roslan, Claudia Eggstein, Jule Focken, Tiago Granja, Vasudharani Devanathan, Birgit Schittek, Robert Lukowski, Bettina Weigelin, Peter Rosenberger, Bernd Nürnberg, Sandra Beer-Hammer","doi":"10.1007/s00395-024-01057-x","DOIUrl":"https://doi.org/10.1007/s00395-024-01057-x","url":null,"abstract":"<p><p>Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα<sub>i</sub> proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα<sub>i2</sub> proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα<sub>i2</sub> in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2<sup>-/-</sup> → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gα<sub>i2</sub> in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2<sup>-/-</sup> vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gα<sub>i2</sub> for mIRI. Here, we show that infarct size was substantially reduced when Gα<sub>i2</sub> signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2<sup>fl/fl</sup> LysM-Cre<sup>+/tg</sup> vs 42.0% Gnai2<sup>fl/fl</sup>; p < 0.01) or selectively blocked with specific antibodies directed against Gα<sub>i2</sub> (AAR: 19.0% (anti-Gα<sub>i2</sub>) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2<sup>fl/fl</sup>; LysM-Cre<sup>+/tg</sup>) vs 31 (Gnai2<sup>fl/fl</sup>); p < 0.001) and in anti-Gα<sub>i2</sub> antibody-treated (PNCs: 9 (anti-Gα<sub>i2</sub>) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα<sub>i2</sub> antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα<sub>i2</sub> antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gα<sub>i2</sub>) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gα<sub>i2</sub> inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-25DOI: 10.1007/s00395-024-01055-z
R. W. A. van Drie, J. van de Wouw, L. M. Zandbergen, J. Dehairs, J. V. Swinnen, M. T. Mulder, M. C. Verhaar, A. MaassenVanDenBrink, D. J. Duncker, O. Sorop, D. Merkus
Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg−1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.
{"title":"Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities","authors":"R. W. A. van Drie, J. van de Wouw, L. M. Zandbergen, J. Dehairs, J. V. Swinnen, M. T. Mulder, M. C. Verhaar, A. MaassenVanDenBrink, D. J. Duncker, O. Sorop, D. Merkus","doi":"10.1007/s00395-024-01055-z","DOIUrl":"https://doi.org/10.1007/s00395-024-01055-z","url":null,"abstract":"<p>Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET<sub>A+B</sub>-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg<sup>−1</sup> i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H<sub>2</sub>O<sub>2</sub> acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET<sub>A+B</sub> blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H<sub>2</sub>O<sub>2</sub>-mediated coronary vasodilation.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141098033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.
{"title":"Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.","authors":"Sourav Kundu, Shobhit Gairola, Smriti Verma, Madhav Nilakanth Mugale, Bidya Dhar Sahu","doi":"10.1007/s00395-024-01056-y","DOIUrl":"https://doi.org/10.1007/s00395-024-01056-y","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1007/s00395-024-01051-3
Ling Li, Bernd Niemann, Fabienne Knapp, Sebastian Werner, Christian Mühlfeld, Jan Philipp Schneider, Liane M. Jurida, Nicole Molenda, M. Lienhard Schmitz, Xiaoke Yin, Manuel Mayr, Rainer Schulz, Michael Kracht, Susanne Rohrbach
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.
{"title":"Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat","authors":"Ling Li, Bernd Niemann, Fabienne Knapp, Sebastian Werner, Christian Mühlfeld, Jan Philipp Schneider, Liane M. Jurida, Nicole Molenda, M. Lienhard Schmitz, Xiaoke Yin, Manuel Mayr, Rainer Schulz, Michael Kracht, Susanne Rohrbach","doi":"10.1007/s00395-024-01051-3","DOIUrl":"https://doi.org/10.1007/s00395-024-01051-3","url":null,"abstract":"<p>The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}