Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiac alterations, but the mechanisms remain elusive. Both breast cancer and DOX therapy are associated with dyslipidemia. We aimed to investigate whether changes in high-density lipoprotein (HDL) particles subclass distribution and functionalities are associated with DOX-induced cardiac alterations in breast cancer patients and tumor-bearing mice. HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n = 34) and tumor-bearing mice at baseline and after receiving DOX chemotherapy. HDL particles antioxidative properties were assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells. In breast cancer patients, DOX therapy reduced intermediate HDL particles subclasses, an effect that positively correlated with cardiac alterations. In mice, breast cancer shifted HDL particles subclasses distribution from intermediate to large HDL particles while DOX therapy increased small HDL particles. Both breast cancer and DOX therapy were associated with reduced PON1 activity. The decrease in intermediate HDL particles correlated with poorer cardiac function and lower PON1 activity. Interestingly, HDL particles isolated from tumor-bearing mice or from mice receiving DOX failed to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice. In our study, a shift in HDL particles subclasses and functionalities correlated with cardiac alterations in cancer patients and mice treated with DOX. Consequently, our data warrant further research to explore whether targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.
{"title":"Dysfunctional high-density lipoprotein particles are associated with cardiac alterations in cancer patients and tumor-bearing mice receiving doxorubicin.","authors":"Carmelita Abrahams,Wanzhu Zhang,Nonhlakanipho Sangweni,Vitaris Kodogo,Nkanyiso Hadebe,Emmy Okello,Rabia Johnson,Nicholas J Woudberg,Karen Sliwa,Sandrine Lecour","doi":"10.1007/s00395-025-01149-2","DOIUrl":"https://doi.org/10.1007/s00395-025-01149-2","url":null,"abstract":"Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiac alterations, but the mechanisms remain elusive. Both breast cancer and DOX therapy are associated with dyslipidemia. We aimed to investigate whether changes in high-density lipoprotein (HDL) particles subclass distribution and functionalities are associated with DOX-induced cardiac alterations in breast cancer patients and tumor-bearing mice. HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n = 34) and tumor-bearing mice at baseline and after receiving DOX chemotherapy. HDL particles antioxidative properties were assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells. In breast cancer patients, DOX therapy reduced intermediate HDL particles subclasses, an effect that positively correlated with cardiac alterations. In mice, breast cancer shifted HDL particles subclasses distribution from intermediate to large HDL particles while DOX therapy increased small HDL particles. Both breast cancer and DOX therapy were associated with reduced PON1 activity. The decrease in intermediate HDL particles correlated with poorer cardiac function and lower PON1 activity. Interestingly, HDL particles isolated from tumor-bearing mice or from mice receiving DOX failed to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice. In our study, a shift in HDL particles subclasses and functionalities correlated with cardiac alterations in cancer patients and mice treated with DOX. Consequently, our data warrant further research to explore whether targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"25 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644952","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 : 2025-12-01Epub Date: 2025-11-11DOI: 10.1007/s00395-025-01145-6
Zilong Xiao, Xiang Wei, Zhonglei Xie, Qingxing Chen, Ruizhen Chen, Ziqing Yu, Yixiu Liang, Yangang Su, Junbo Ge
Mixed lineage kinase 3 (MLK3), a member of the MAP3K family, is known to participate in cellular stress and inflammatory responses, but its role in neutrophil-mediated myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, we investigated the function and downstream signaling of MLK3 in neutrophils using genetically modified mouse models with neutrophil-specific MLK3 knockout or overexpression. MLK3 deficiency in neutrophils reduced infarct size, improved cardiac function, and decreased neutrophil infiltration, NET formation, and pro-inflammatory cytokine release following I/R. Transcriptomic profiling revealed that MLK3 promotes the expression of the antimicrobial peptide CRAMP by stabilizing and activating the transcription factor C/EBPβ. Administration of exogenous CRAMP abolished the protective effects of MLK3 deletion, confirming its functional relevance. Furthermore, treatment with CEP-1347, a small-molecule MLK3 inhibitor, attenuated myocardial injury, reduced apoptosis, and limited adverse remodeling in vivo. In acute myocardial infarction (AMI) patients, elevated levels of phosphorylated MLK3 (pMLK3) in circulating neutrophils were associated with increased levels of MPO-DNA, cTnT, and CK-MB, as well as a trend toward higher rates of cardiovascular rehospitalization. These findings identify a neutrophil-intrinsic MLK3-C/EBPβ-CRAMP axis that amplifies myocardial inflammation and injury, and suggest MLK3 as a promising therapeutic target and potential biomarker for ischemic heart disease.
混合谱系激酶3 （MLK3）是MAP3K家族的一员，已知参与细胞应激和炎症反应，但其在中性粒细胞介导的心肌缺血再灌注（I/R）损伤中的作用尚不清楚。在这项研究中，我们通过中性粒细胞特异性MLK3敲除或过表达的转基因小鼠模型研究了MLK3在中性粒细胞中的功能和下游信号传导。中性粒细胞MLK3缺乏减少梗死面积，改善心功能，减少I/R后中性粒细胞浸润、NET形成和促炎细胞因子释放。转录组学分析显示，MLK3通过稳定和激活转录因子C/EBPβ来促进抗菌肽CRAMP的表达。外源性camp消除了MLK3缺失的保护作用，证实了其功能相关性。此外，CEP-1347（一种小分子MLK3抑制剂）治疗可减轻心肌损伤，减少细胞凋亡，并限制体内不良重构。在急性心肌梗死（AMI）患者中，循环中性粒细胞中磷酸化MLK3 （pMLK3）水平升高与MPO-DNA、cTnT和CK-MB水平升高相关，并有心血管再住院率升高的趋势。这些发现确定了中性粒细胞内生性MLK3- c /EBPβ-CRAMP轴可放大心肌炎症和损伤，并提示MLK3是一种有希望的治疗靶点和缺血性心脏病的潜在生物标志物。
{"title":"Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation.","authors":"Zilong Xiao, Xiang Wei, Zhonglei Xie, Qingxing Chen, Ruizhen Chen, Ziqing Yu, Yixiu Liang, Yangang Su, Junbo Ge","doi":"10.1007/s00395-025-01145-6","DOIUrl":"10.1007/s00395-025-01145-6","url":null,"abstract":"<p><p>Mixed lineage kinase 3 (MLK3), a member of the MAP3K family, is known to participate in cellular stress and inflammatory responses, but its role in neutrophil-mediated myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, we investigated the function and downstream signaling of MLK3 in neutrophils using genetically modified mouse models with neutrophil-specific MLK3 knockout or overexpression. MLK3 deficiency in neutrophils reduced infarct size, improved cardiac function, and decreased neutrophil infiltration, NET formation, and pro-inflammatory cytokine release following I/R. Transcriptomic profiling revealed that MLK3 promotes the expression of the antimicrobial peptide CRAMP by stabilizing and activating the transcription factor C/EBPβ. Administration of exogenous CRAMP abolished the protective effects of MLK3 deletion, confirming its functional relevance. Furthermore, treatment with CEP-1347, a small-molecule MLK3 inhibitor, attenuated myocardial injury, reduced apoptosis, and limited adverse remodeling in vivo. In acute myocardial infarction (AMI) patients, elevated levels of phosphorylated MLK3 (pMLK3) in circulating neutrophils were associated with increased levels of MPO-DNA, cTnT, and CK-MB, as well as a trend toward higher rates of cardiovascular rehospitalization. These findings identify a neutrophil-intrinsic MLK3-C/EBPβ-CRAMP axis that amplifies myocardial inflammation and injury, and suggest MLK3 as a promising therapeutic target and potential biomarker for ischemic heart disease.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"1155-1171"},"PeriodicalIF":8.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145487634","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 : 2025-12-01DOI: 10.1007/s00395-025-01142-9
Sauri Hernandez-Resendiz, Reinis Vilskersts, David Aluja, Ioanna Andreadou, Péter Bencsik, Maija Dambrova, Panagiotis Efentakis, Fei Gao, Zoltán Giricz, Gábor B Brenner, Nabil V Sayour, Tamás G Gergely, András Makkos, Javier Inserte, Roisin Kelly-Laubscher, Attila Kiss, Thomas Krieg, Brenda R Kwak, Sandrine Lecour, Gary Lopaschuk, Michał Mączewski, Michał Waszkiewicz, Marta Oknińska, Pasquale Pagliaro, Bruno Podesser, Hiran A Prag, Marisol Ruiz-Meana, Tamara Szabados, Coert J Zuurbier, Péter Ferdinandy, Derek J Hausenloy
{"title":"Correction: IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT): a small animal acute myocardial infarction randomized-controlled multicenter study on the effect of ischemic preconditioning.","authors":"Sauri Hernandez-Resendiz, Reinis Vilskersts, David Aluja, Ioanna Andreadou, Péter Bencsik, Maija Dambrova, Panagiotis Efentakis, Fei Gao, Zoltán Giricz, Gábor B Brenner, Nabil V Sayour, Tamás G Gergely, András Makkos, Javier Inserte, Roisin Kelly-Laubscher, Attila Kiss, Thomas Krieg, Brenda R Kwak, Sandrine Lecour, Gary Lopaschuk, Michał Mączewski, Michał Waszkiewicz, Marta Oknińska, Pasquale Pagliaro, Bruno Podesser, Hiran A Prag, Marisol Ruiz-Meana, Tamara Szabados, Coert J Zuurbier, Péter Ferdinandy, Derek J Hausenloy","doi":"10.1007/s00395-025-01142-9","DOIUrl":"10.1007/s00395-025-01142-9","url":null,"abstract":"","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"1249-1250"},"PeriodicalIF":8.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12680880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145480570","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 : 2025-11-28DOI: 10.1007/s00395-025-01150-9
Luo Liu,Rongling Wang,Stefano Strocchi,Tolga Eroglu,Natasha Nambiar,Sarah V Liévano Contreras,Saskia A Diezel,Gabriele G Schiattarella
Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its prevalence is projected to rise further. Among its heterogeneous subtypes, cardiometabolic HFpEF, which is driven by metabolic dysfunction, represents a globally predominant form. Recent advances in preclinical models have highlighted metabolic disturbances and systemic inflammation as key contributors to HFpEF pathogenesis. While much attention has focused on classical inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the full spectrum of upstream inflammatory drivers and the therapeutic strategies targeting inflammation in cardiometabolic HFpEF remain incompletely defined. Among emerging candidates, serum amyloid A (SAA) family proteins, highly inducible acute-phase proteins, have attracted growing attention due to their elevated levels in chronic metabolic diseases. Here, we summarize clinical associations between elevated SAA levels and major cardiometabolic conditions-including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and hypertension-and discuss potential mechanisms based on preclinical studies. We place particular emphasis on the known and potential pathogenetic role of SAA in cardiometabolic HFpEF, where it may contribute to systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Overall, this review aims to advance understanding of SAA in HFpEF and cardiometabolic disease, and to support translational efforts toward improved diagnosis and treatment.
{"title":"Serum amyloid A in HFpEF and cardiometabolic diseases.","authors":"Luo Liu,Rongling Wang,Stefano Strocchi,Tolga Eroglu,Natasha Nambiar,Sarah V Liévano Contreras,Saskia A Diezel,Gabriele G Schiattarella","doi":"10.1007/s00395-025-01150-9","DOIUrl":"https://doi.org/10.1007/s00395-025-01150-9","url":null,"abstract":"Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, and its prevalence is projected to rise further. Among its heterogeneous subtypes, cardiometabolic HFpEF, which is driven by metabolic dysfunction, represents a globally predominant form. Recent advances in preclinical models have highlighted metabolic disturbances and systemic inflammation as key contributors to HFpEF pathogenesis. While much attention has focused on classical inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), the full spectrum of upstream inflammatory drivers and the therapeutic strategies targeting inflammation in cardiometabolic HFpEF remain incompletely defined. Among emerging candidates, serum amyloid A (SAA) family proteins, highly inducible acute-phase proteins, have attracted growing attention due to their elevated levels in chronic metabolic diseases. Here, we summarize clinical associations between elevated SAA levels and major cardiometabolic conditions-including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), and hypertension-and discuss potential mechanisms based on preclinical studies. We place particular emphasis on the known and potential pathogenetic role of SAA in cardiometabolic HFpEF, where it may contribute to systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Overall, this review aims to advance understanding of SAA in HFpEF and cardiometabolic disease, and to support translational efforts toward improved diagnosis and treatment.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"146 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613279","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 : 2025-11-22DOI: 10.1007/s00395-025-01147-4
Sean O Bello,Charanjit Singh,Filippo Perbellini,Prakash P Punjabi,Cesare M Terracciano
Percutaneous left ventricular assist devices (LVADs) have become essential tools during coronary reperfusion in high-risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 min (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart-lung transplantation. The recipient's heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p = 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6% and 3.7%, respectively, after permanent ligation, and 0.5% and 10.4%, respectively, after coronary reperfusion. These data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction.
经皮左心室辅助装置（lvad）已成为高危PCI患者冠状动脉再灌注的重要工具。当机械卸载与再灌注相结合时，可以观察到梗死扩展的显著减少，但对于lvad的壁应力和细胞外基质的减少对心脏再生能力的影响知之甚少。本研究探讨冠状动脉再灌注联合机械卸载对心肌纤维化的影响，以及细胞外基质的这些变化对心脏再生潜能的影响。Lewis大鼠冠状动脉结扎诱导心肌梗死。心脏接受永久性冠状动脉结扎（AMI）或90分钟后再灌注（AMI/R）。在每一组中，心脏要么有负荷（AMI- l或AMI/R-L），要么没有负荷（AMI- u或AMI/R-U）。在无负荷亚组，梗死心脏在90分钟后被移植，通过异位腹部心肺移植移植到健康受者的腹部。接受者的心脏作为对照。第7天进行心脏分析。研究了30颗心脏。在永久性结扎组，心肌细胞增殖无明显增加，但心肌纤维化在负荷和未负荷心脏均有所增加。冠状动脉再灌注后，机械卸载未观察到纤维化增加，但心肌细胞增殖明显增加（AMI/R-L vs AMI/R-U p = 0.0001）。冠脉再灌注后，心肌细胞增殖率分别为0.5%和10.4%。永久性结扎后，心肌细胞增殖率为0.6%和3.7%。这些数据表明，冠脉再灌注联合机械卸载可减少心肌纤维化，上调心肌梗死后心肌细胞增殖。
{"title":"Mechanical unloading coupled with coronary reperfusion stimulates cardiomyocyte proliferation and prevents unloading-induced fibrosis after myocardial infarction.","authors":"Sean O Bello,Charanjit Singh,Filippo Perbellini,Prakash P Punjabi,Cesare M Terracciano","doi":"10.1007/s00395-025-01147-4","DOIUrl":"https://doi.org/10.1007/s00395-025-01147-4","url":null,"abstract":"Percutaneous left ventricular assist devices (LVADs) have become essential tools during coronary reperfusion in high-risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with LVADs has on the heart's regenerative capacity. This study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact of these changes in extracellular matrix on the heart's regenerative potential. MI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 min (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 min and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart-lung transplantation. The recipient's heart acted as control. Hearts were analysed on day 7. 30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, no increase in fibrosis was observed with mechanical unloading but cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p = 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6% and 3.7%, respectively, after permanent ligation, and 0.5% and 10.4%, respectively, after coronary reperfusion. These data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"4 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568141","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 : 2025-11-20DOI: 10.1007/s00395-025-01148-3
Salman I Essajee,Gregory M Dick,Selina M Tucker,Cooper M Warne,C Alberto Figueroa,Daniel A Beard,Dirk J Duncker,Johnathan D Tune
Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO2) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K+ channels with 4-aminopyridine (4-AP; 1 mM, ic). Reduction of CPP to 40 mmHg diminished coronary flow (~ 55%; P < 0.001) and systolic wall thickening (~ 35%; P < 0.001). 4-AP-mediated reductions in coronary flow (~ 35%; P = 0.01) and wall thickening (~ 40%; P < 0.05) were restored by returning coronary flow to normal baseline levels. Dobutamine increased heart rate and coronary flow ~ 65% (P < 0.001) and coronary flow remained tightly coupled with MVO2. Inhibition of coronary responses to dobutamine was associated with an ~ 35% reduction in wall thickening and an ~ 50% increase in MVO2. Reductions in CPP, administration of 4-AP, and diminished flow during dobutamine infusion were associated with proportional decreases in coronary flow and MVO2. Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished "supply" (CPP, 4-AP) or limitations during increased "demand" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat.
{"title":"Impairment of local metabolic coronary control involves perfusion-contraction matching not supply-demand imbalance.","authors":"Salman I Essajee,Gregory M Dick,Selina M Tucker,Cooper M Warne,C Alberto Figueroa,Daniel A Beard,Dirk J Duncker,Johnathan D Tune","doi":"10.1007/s00395-025-01148-3","DOIUrl":"https://doi.org/10.1007/s00395-025-01148-3","url":null,"abstract":"Understanding of local metabolic control of coronary flow remains stifled by debate around data interpretation and anticipated outcomes. To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO2) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K+ channels with 4-aminopyridine (4-AP; 1 mM, ic). Reduction of CPP to 40 mmHg diminished coronary flow (~ 55%; P < 0.001) and systolic wall thickening (~ 35%; P < 0.001). 4-AP-mediated reductions in coronary flow (~ 35%; P = 0.01) and wall thickening (~ 40%; P < 0.05) were restored by returning coronary flow to normal baseline levels. Dobutamine increased heart rate and coronary flow ~ 65% (P < 0.001) and coronary flow remained tightly coupled with MVO2. Inhibition of coronary responses to dobutamine was associated with an ~ 35% reduction in wall thickening and an ~ 50% increase in MVO2. Reductions in CPP, administration of 4-AP, and diminished flow during dobutamine infusion were associated with proportional decreases in coronary flow and MVO2. Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished \"supply\" (CPP, 4-AP) or limitations during increased \"demand\" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"1 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559204","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 : 2025-11-14DOI: 10.1007/s00395-025-01146-5
William E Hughes,Shelby N Hader,Kate Astbury,Lukas Brandt,Karima Ait-Aissa,David D Gutterman,Andreas M Beyer
The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.
{"title":"Autophagy modulates the mechanism of flow-mediated dilation upstream of telomerase.","authors":"William E Hughes,Shelby N Hader,Kate Astbury,Lukas Brandt,Karima Ait-Aissa,David D Gutterman,Andreas M Beyer","doi":"10.1007/s00395-025-01146-5","DOIUrl":"https://doi.org/10.1007/s00395-025-01146-5","url":null,"abstract":"The non-canonical functions of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase play a critical role in maintaining microvascular homeostasis utilizing both human and rodent models. Previously, we have demonstrated that intact autophagic flux is necessary for the beneficial effects of TERT to maintain microvascular function and redox status in human resistance arterioles. The purpose of this investigation was to examine (1) whether loss of TERT function in vivo resulted in reductions in autophagy/mitophagy and concomitant changes in the mediator of microvascular FMD; (2) whether restoration of autophagy can reverse this pathological switch in dilator mechanism, reduce shear-induced mitochondrial H2O2 production while enhancing NO production. TERT mutant rats were generated and compared to their WT counterparts. Rats were given an autophagy activator (2% trehalose) for 28-days. Isolated mesenteric arteries were used for videomicroscopy, and aortic tissue was collected for immunoblotting. FMD and autophagic flux were measured in arteries in all groups. Loss of TERT function resulted in a switch from NOS-dependent to H2O2-dependent FMD, repressed microvascular shear-induced autophagic flux and NO production, and increased mitochondrial H2O2 production. Activation of autophagy restored NO-mediated dilation in TERT mutant rats, and enhanced shear-induced autophagic flux. We provide evidence that autophagy is necessary for the beneficial role of TERT within maintaining microvascular function, positioning this pathway as a modifiable target to maintain microvascular health by rescuing the endothelial dysfunction caused by loss of TERT signaling.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"92 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516265","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 : 2025-11-07DOI: 10.1007/s00395-025-01144-7
Patricia E McCallinhart,Corinne H Strawser,Elizabeth A R Garfinkle,Jaye B Navarro,Cynthia McAllister,Tatyana A Vetter,Pamela A Lucchesi,Elaine R Mardis,Louisa Mezache,Rengasayee Veeraraghavan,Katherine E Miller,Aaron J Trask
Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle function, vascular remodeling, and alterations in mechanics. These culminate in impaired coronary blood flow. To interrogate transcriptional differences potentially contributing to CMD, we tested the hypothesis that comprehensive single-cell and spatial transcriptomic profiling of the coronary microcirculation and surrounding myocardium will identify new pathways to target in CMD. We utilized an innovative combination of single-cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Single-cell RNA profiling and spatial transcriptomics revealed an upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. In ECs, VSMCs, cardiomyocyte clusters, fibroblasts, and macrophages, the upregulation of adipogenesis was directed by Angplt4 and Ephx2, whereas Hmgcs2 and Acot2 were the key players in the upregulation of fatty acid metabolism, and Pdk4 and Ech1 were the drivers of oxidative phosphorylation upregulation. These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D heart failure-characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization-contributes to oxidative stress and lipotoxicity. Our data unveiled novel and unique gene expression signatures of coronary microvessels in the presence and absence of diabetes.
{"title":"Single cell and spatial transcriptomic profiling of the type 2 diabetic coronary microcirculation and myocardium.","authors":"Patricia E McCallinhart,Corinne H Strawser,Elizabeth A R Garfinkle,Jaye B Navarro,Cynthia McAllister,Tatyana A Vetter,Pamela A Lucchesi,Elaine R Mardis,Louisa Mezache,Rengasayee Veeraraghavan,Katherine E Miller,Aaron J Trask","doi":"10.1007/s00395-025-01144-7","DOIUrl":"https://doi.org/10.1007/s00395-025-01144-7","url":null,"abstract":"Coronary microvascular disease (CMD) is an early complication of type 2 diabetes (T2D) involving adverse endothelial and smooth muscle function, vascular remodeling, and alterations in mechanics. These culminate in impaired coronary blood flow. To interrogate transcriptional differences potentially contributing to CMD, we tested the hypothesis that comprehensive single-cell and spatial transcriptomic profiling of the coronary microcirculation and surrounding myocardium will identify new pathways to target in CMD. We utilized an innovative combination of single-cell RNA profiling and spatial transcriptomics to examine transcriptional differences and molecular signatures of CMD in T2D mice. Single-cell RNA profiling and spatial transcriptomics revealed an upregulation of genes linked to adipogenesis, fatty acid metabolism, and oxidative phosphorylation in T2D cell clusters and coronary microvascular-enriched regions. In ECs, VSMCs, cardiomyocyte clusters, fibroblasts, and macrophages, the upregulation of adipogenesis was directed by Angplt4 and Ephx2, whereas Hmgcs2 and Acot2 were the key players in the upregulation of fatty acid metabolism, and Pdk4 and Ech1 were the drivers of oxidative phosphorylation upregulation. These intriguing data support the well-documented concept that cardiac metabolic inflexibility in T2D heart failure-characterized by reduced mitochondrial function, increased reliance on fatty acid oxidation, and impaired glucose utilization-contributes to oxidative stress and lipotoxicity. Our data unveiled novel and unique gene expression signatures of coronary microvessels in the presence and absence of diabetes.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"161 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462005","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 : 2025-11-01DOI: 10.1007/s00395-025-01143-8
Kostiantyn Drachuk,Yoshinori Nishijima,Aravind Parthasarathy,Yangjing Xie,Sneha Nagavally,Aprill Dawson,David D Gutterman,David X Zhang
This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60 mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H2O2 scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H2O2-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H2O2 significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H2O2-mediated response. In CAD, the contribution of both NO and H2O2 is diminished, while an NO/H2O2-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.
{"title":"The role of NO, H2O2, and non-NO/H2O2 mechanisms in acetylcholine (ACh)-induced dilation of human arterioles in the absence and presence of coronary artery disease.","authors":"Kostiantyn Drachuk,Yoshinori Nishijima,Aravind Parthasarathy,Yangjing Xie,Sneha Nagavally,Aprill Dawson,David D Gutterman,David X Zhang","doi":"10.1007/s00395-025-01143-8","DOIUrl":"https://doi.org/10.1007/s00395-025-01143-8","url":null,"abstract":"This study defines the mechanisms of vasodilation to acetylcholine (ACh) in arterioles from patients with and without coronary artery disease (CAD). Human adipose arterioles (HAA) dissected from discarded surgical samples were cannulated and pressurized at 60 mmHg for measurement of diameter changes by videomicroscopy. No difference in baseline dose response to ACh was observed between non-CAD and CAD patients. L-NAME, NO synthase inhibitor, reduced dilation in both groups but to a greater extent in non-CAD. Peg-CAT, H2O2 scavenger, attenuated response to ACh in non-CAD but not in CAD. Inhibition of NOX4 reduced dilation in non-CAD, whereas NOX2 inhibition attenuated dilation in CAD. The SOD mimetic tempol partially normalized the NO- and H2O2-dependent dilation in CAD arterioles. EPR spin trapping indicated that absolute NO signal after ACh + A-23187 stimulation was higher in non-CAD than in CAD arteries. Western blot analysis revealed higher expression of monomeric eNOS but lower expression of dimeric eNOS and phosphorylated eNOS at Ser-1177 in CAD arteries. Finally, we found higher mRNA and protein expression of NOX2 in CAD arteries. These results provide new evidence that in normal human arterioles, both NO and H2O2 significantly contribute to ACh dilation, with substantial involvement of NOX4 in the H2O2-mediated response. In CAD, the contribution of both NO and H2O2 is diminished, while an NO/H2O2-independent hyperpolarizing pathway becomes predominant. Mechanistically, the NOX4-to-NOX2 switch may play a key role in mediating the change of vasodilator mechanisms in human arterioles during CAD.","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"90 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145424159","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 : 2025-10-01Epub Date: 2025-08-22DOI: 10.1007/s00395-025-01133-w
P R Goody, D Christmann, D Goody, S Hildebrand, H Billig, D Nehl, R Chennupati, M Gladka, K Wilhelm-Jüngling, S Uchida, S Iris-Bibli, J B Moore, N Hamdani, F Paneni, S S Pullamsetti, S Zimmer, F Jansen, F Bakhtiary, E Aikawa, A Pfeifer, G Nickenig, M R Hosen
<p><p>Calcific aortic valve disease (CAVD) is one of the leading causes of cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with CAVD undergoing surgical aortic valve replacement (SAVR). However, the miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crosstalk during the pathogenesis of CAVD remain poorly understood. Here, we investigated the role of extracellular vesicle (EV)-associated miR-145-5p, which we showed to be strongly upregulated in CAVD in mice and humans during valve calcification. Human TaqMan miRNA arrays identified dysregulated miRNAs in CAVD tissue explants from patients compared to non-calcified (patients with aortic insufficiency) heart valve tissue explants from patients undergoing SAVR. Echocardiographic parameters were measured in conjunction with the quantification of dysregulated miRNAs in a murine CAVD model. In vitro calcification experiments were performed to investigate the effects of EV-miR-145-5p on calcification and crosstalk in heart valve cells. Integrated OMICS analyses were performed to analyze molecular miRNA signatures and their effects on signaling pathways-associated with CAVD. RNA sequencing, high-throughput transcription factor (TF) activity assays, and osteogenesis arrays revealed that a number of genes, miRNAs, TFs are critical for calcification and apoptosis involved in the pathogenesis of CAVD. Among several miRNAs dysregulated in valve explants from CAVD patients, miR-145-5p was the most highly sex-independently upregulated miRNA (AUC, 0.780, p value, 0.01) in patient plasma. Large EV population (170-800 nm) isolated from aortic valve tissues explanted from patients with CAVS (calcific aortic valve stenosis) after SAVR demonstrated a significantly higher level of miR-145-5p expression in comparison to control (vesicle-free plasma). MiRNA arrays utilizing with aortic stenosis samples from patients and mice showed that the expression of miR-145-5p is significantly upregulated and positively correlated with cardiac function based on echocardiography. In vitro experiments confirmed that miR-145-5p is encapsulated in EVs and transported into interstitial cells of the aortic valve. The results of integrated OMICs show that miR-145-5p is related to markers of inflammation, calcification, and apoptosis. In vitro calcification experiments demonstrated that miR-145-5p regulates the ALPL gene, a hallmark of calcification in vascular and heart valve cells. Mechanistically, EV-mediated shuttling of miR-145-5p suppressed the expression of ZEB2, a negative regulator of the ALPL gene, by binding to its 3' untranslated region to inhibit its translation, thereby diminishing the calcification of valvular interstitial cells. Elevated levels of pro-calcific and pro-apoptotic EV-associated miR-145-5p contribute to the progression of CAVD via the ZEB2-ALPL axis, which could potentially be therapeutically targeted t
{"title":"Calcific aortic valve disease augments vesicular microRNA-145-5p to regulate the calcification of valvular interstitial cells via cellular crosstalk.","authors":"P R Goody, D Christmann, D Goody, S Hildebrand, H Billig, D Nehl, R Chennupati, M Gladka, K Wilhelm-Jüngling, S Uchida, S Iris-Bibli, J B Moore, N Hamdani, F Paneni, S S Pullamsetti, S Zimmer, F Jansen, F Bakhtiary, E Aikawa, A Pfeifer, G Nickenig, M R Hosen","doi":"10.1007/s00395-025-01133-w","DOIUrl":"10.1007/s00395-025-01133-w","url":null,"abstract":"<p><p>Calcific aortic valve disease (CAVD) is one of the leading causes of cardiovascular death in the elderly population worldwide. MicroRNAs (miRNAs) are highly dysregulated in patients with CAVD undergoing surgical aortic valve replacement (SAVR). However, the miRNA-dependent mechanisms regulating inflammation and calcification or miRNA-mediated cell-cell crosstalk during the pathogenesis of CAVD remain poorly understood. Here, we investigated the role of extracellular vesicle (EV)-associated miR-145-5p, which we showed to be strongly upregulated in CAVD in mice and humans during valve calcification. Human TaqMan miRNA arrays identified dysregulated miRNAs in CAVD tissue explants from patients compared to non-calcified (patients with aortic insufficiency) heart valve tissue explants from patients undergoing SAVR. Echocardiographic parameters were measured in conjunction with the quantification of dysregulated miRNAs in a murine CAVD model. In vitro calcification experiments were performed to investigate the effects of EV-miR-145-5p on calcification and crosstalk in heart valve cells. Integrated OMICS analyses were performed to analyze molecular miRNA signatures and their effects on signaling pathways-associated with CAVD. RNA sequencing, high-throughput transcription factor (TF) activity assays, and osteogenesis arrays revealed that a number of genes, miRNAs, TFs are critical for calcification and apoptosis involved in the pathogenesis of CAVD. Among several miRNAs dysregulated in valve explants from CAVD patients, miR-145-5p was the most highly sex-independently upregulated miRNA (AUC, 0.780, p value, 0.01) in patient plasma. Large EV population (170-800 nm) isolated from aortic valve tissues explanted from patients with CAVS (calcific aortic valve stenosis) after SAVR demonstrated a significantly higher level of miR-145-5p expression in comparison to control (vesicle-free plasma). MiRNA arrays utilizing with aortic stenosis samples from patients and mice showed that the expression of miR-145-5p is significantly upregulated and positively correlated with cardiac function based on echocardiography. In vitro experiments confirmed that miR-145-5p is encapsulated in EVs and transported into interstitial cells of the aortic valve. The results of integrated OMICs show that miR-145-5p is related to markers of inflammation, calcification, and apoptosis. In vitro calcification experiments demonstrated that miR-145-5p regulates the ALPL gene, a hallmark of calcification in vascular and heart valve cells. Mechanistically, EV-mediated shuttling of miR-145-5p suppressed the expression of ZEB2, a negative regulator of the ALPL gene, by binding to its 3' untranslated region to inhibit its translation, thereby diminishing the calcification of valvular interstitial cells. Elevated levels of pro-calcific and pro-apoptotic EV-associated miR-145-5p contribute to the progression of CAVD via the ZEB2-ALPL axis, which could potentially be therapeutically targeted t","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"991-1010"},"PeriodicalIF":8.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12518376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940654","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}
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