Pub Date : 2025-07-11DOI: 10.1016/j.yjmcc.2025.07.008
Daphne Diloretto , Gaurav Sarode , Phung N. Thai , Jeong Han Lee , Evelyn Navar , Jeong eun Park , Chaitali Khadilkar , Ning Zong , Yu Jia Dong , Avni Duda , Erick Romero , Pablo E. Acevedo , Xiao-Dong Zhang , David A. Liem , Imo Ebong , Javier E. Lopez , Heejung Bang , Chao-Yin Chen , Leighton Izu , Martin Cadeiras , Padmini Sirish
Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [1,2]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.
{"title":"Psychosocial stress amplifies inflammation through NLRP3 Inflammasome activated by endoplasmic reticulum stress in the mouse heart","authors":"Daphne Diloretto , Gaurav Sarode , Phung N. Thai , Jeong Han Lee , Evelyn Navar , Jeong eun Park , Chaitali Khadilkar , Ning Zong , Yu Jia Dong , Avni Duda , Erick Romero , Pablo E. Acevedo , Xiao-Dong Zhang , David A. Liem , Imo Ebong , Javier E. Lopez , Heejung Bang , Chao-Yin Chen , Leighton Izu , Martin Cadeiras , Padmini Sirish","doi":"10.1016/j.yjmcc.2025.07.008","DOIUrl":"10.1016/j.yjmcc.2025.07.008","url":null,"abstract":"<div><div>Psychosocial stress (PSS) affects all humans with different intensities and is known to significantly increase inflammation and cardiovascular disease [<span><span>1</span></span>,<span><span>2</span></span>]. An amplifier of inflammation is an intracellular multiprotein complex, the inflammasome, activation of which leads to pro-inflammatory cytokines production. However, the mechanisms leading to the inflammasome activation in the heart by PSS are not well understood. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum (ER) stress and JAK/STAT pathway. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to PSS.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 39-43"},"PeriodicalIF":4.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.yjmcc.2025.07.007
Girish C. Melkani
Circadian rhythm is critical in maintaining metabolic homeostasis, including cardiac health, with disruptions often leading to adverse cardiac outcomes. Time-restricted feeding/eating (TRF/TRE) is a dietary approach that limits food intake to specific hours during an organism's active phase, daytime for diurnal animals and nighttime for nocturnal ones. This strategy has shown promise in realigning circadian rhythms and reducing the negative effects of circadian disruption on heart function. This review examines the intricate relationship between circadian rhythms and cardiac health, highlighting the molecular mechanisms governed by central and peripheral clocks. We discuss how circadian misalignment contributes to cardiovascular disease and explore how TRF/TRE can restore circadian synchronization, particularly in the context of lipid metabolism, gene expression, and other physiological processes essential for heart function. The review also examines the impact of TRF/TRE on cardiac renovation, particularly under conditions of circadian disruption associated with cardiovascular and cardiometabolic disorders. We further explore potential molecular mechanisms, including the modulation of clock genes and lipid metabolic pathways, such as diacylglycerol O-acyltransferase 2 (DGAT2), that underpin the cardioprotective effects of TRF. By consolidating findings from genetic and translational animal models and human studies, we underscore the promise of TRF/TRE in improving cardiac outcomes and propose areas for future research. The potential of TRF/TRE as a therapeutic intervention for cardiovascular disease warrants further investigation, particularly in understanding its long-term effects on cardiac health and its integration into clinical practice.
{"title":"Time-restricted feeding mediated synchronization of circadian rhythms to sustain cardiovascular health","authors":"Girish C. Melkani","doi":"10.1016/j.yjmcc.2025.07.007","DOIUrl":"10.1016/j.yjmcc.2025.07.007","url":null,"abstract":"<div><div>Circadian rhythm is critical in maintaining metabolic homeostasis, including cardiac health, with disruptions often leading to adverse cardiac outcomes. Time-restricted feeding/eating (TRF/TRE) is a dietary approach that limits food intake to specific hours during an organism's active phase, daytime for diurnal animals and nighttime for nocturnal ones. This strategy has shown promise in realigning circadian rhythms and reducing the negative effects of circadian disruption on heart function. This review examines the intricate relationship between circadian rhythms and cardiac health, highlighting the molecular mechanisms governed by central and peripheral clocks. We discuss how circadian misalignment contributes to cardiovascular disease and explore how TRF/TRE can restore circadian synchronization, particularly in the context of lipid metabolism, gene expression, and other physiological processes essential for heart function. The review also examines the impact of TRF/TRE on cardiac renovation, particularly under conditions of circadian disruption associated with cardiovascular and cardiometabolic disorders. We further explore potential molecular mechanisms, including the modulation of clock genes and lipid metabolic pathways, such as diacylglycerol O-acyltransferase 2 (DGAT2), that underpin the cardioprotective effects of TRF. By consolidating findings from genetic and translational animal models and human studies, we underscore the promise of TRF/TRE in improving cardiac outcomes and propose areas for future research. The potential of TRF/TRE as a therapeutic intervention for cardiovascular disease warrants further investigation, particularly in understanding its long-term effects on cardiac health and its integration into clinical practice.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 1-10"},"PeriodicalIF":4.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144614378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1016/j.yjmcc.2025.07.005
Collin K. Wells , Daniel C. Nguyen , Robert E. Brainard , Lindsey A. McNally , Maleesha De Silva , Kenneth R. Brittian , Lauren Garrett , Madison S. Taylor , Yania Martinez-Ondaro , Caitlin Howard , Snigdha Suluru , Sujith Dassanayaka , Tamer M.A. Mohamed , Richa Singhal , Andrew A. Gibb , Pawel K. Lorkiewicz , Joseph B. Moore IV , Steven P. Jones , Bradford G. Hill
Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although Pck2 deletion had no effect on post-MI remodeling, fibroblast-specific switching of Pkm2 to Pkm1 (fbPkm2 → 1) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fbPkm2 → 1 switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, Pkm2 → 1 splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, Pkm2 → 1 switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.
{"title":"Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice","authors":"Collin K. Wells , Daniel C. Nguyen , Robert E. Brainard , Lindsey A. McNally , Maleesha De Silva , Kenneth R. Brittian , Lauren Garrett , Madison S. Taylor , Yania Martinez-Ondaro , Caitlin Howard , Snigdha Suluru , Sujith Dassanayaka , Tamer M.A. Mohamed , Richa Singhal , Andrew A. Gibb , Pawel K. Lorkiewicz , Joseph B. Moore IV , Steven P. Jones , Bradford G. Hill","doi":"10.1016/j.yjmcc.2025.07.005","DOIUrl":"10.1016/j.yjmcc.2025.07.005","url":null,"abstract":"<div><div>Fibroblasts are crucial for cardiac repair after myocardial infarction (MI). In response to signaling cues, they differentiate to phenotypes with robust capacities to synthesize and secrete extracellular matrix (ECM) and signaling molecules. Although activated fibroblast phenotypes are associated with pronounced changes in metabolism, it remains unclear how the metabolic network upholds the effector functions of fibroblasts in the infarcted heart. We found that two enzymes that could facilitate a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2) and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart after MI. Although <em>Pck2</em> deletion had no effect on post-MI remodeling, fibroblast-specific switching of <em>Pkm2</em> to <em>Pkm1</em> (fb<em>Pkm2 → 1</em>) mitigated ventricular dilation, wall thinning, and losses in ejection fraction caused by MI. Despite these salutary effects, fb<em>Pkm2 → 1</em> switching did not alter cardiac fibrosis in vivo, nor did it affect collagen production, cytokine or chemokine secretion, myofibroblast differentiation markers, or transcriptional regulation in vitro. Nevertheless, <em>Pkm2 → 1</em> splice variant switching increased myofibroblast contractile activity as well as influenced the metabolic phenotype of fibroblasts, as shown by increased pyruvate kinase activity, higher mitochondrial respiratory capacity, and elevation in glycolytic intermediate abundance. Despite these changes, <em>Pkm2 → 1</em> switching had relatively minor effects on glucose carbon fate, as determined by stable isotope-resolved metabolomics. Nevertheless, these metabolic data demonstrate that cardiac fibroblasts exhibit minimal glucose-supported de novo glycine synthesis in vitro, yet possess high hexosamine and glucuronate biosynthetic pathway activity. Collectively, these findings reveal that fibroblast PKM isoforms influence post-MI remodeling, highlighting pyruvate kinase as a potential therapeutic target.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 11-26"},"PeriodicalIF":4.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.
{"title":"Soluble αKlotho interacts with Hsp90aa1 to inhibit the chaperone machinery-mediated Hif1α stabilization and alleviate CKD-induced vascular calcification","authors":"Fengyang Xu , Jialin Guo , Yunyun Guo , Jiaxin Ma , Wentao Sang , Xiangkai Zhao , Jian Zhang , Tonghui Xu , Feng Xu , Yuguo Chen","doi":"10.1016/j.yjmcc.2025.07.003","DOIUrl":"10.1016/j.yjmcc.2025.07.003","url":null,"abstract":"<div><div>Recent studies have highlighted the significance of soluble αKlotho in renal dysfunction-associated vascular health, however, the underlying molecular mechanisms by which soluble αKlotho maintains the vascular smooth muscle cells (VSMCs) phenotype and prevents vascular calcification remain unclear. Clinical analyses revealed an inverse correlation between circulating αKlotho levels and vascular calcification severity in early CKD patients. Recombinant protein or lentiviral vector transfection of soluble αKlotho significantly suppressed the osteogenic transdifferentiation of VSMCs in vitro. AAV-mediated overexpression of soluble αKlotho in VSMCs remarkably reduced vascular calcification without altering circulating soluble αKlotho levels or mineral metabolism in mice under a high-phosphate diet after nephrectomy. We also employed a combination of transcriptomics and proteomics approaches, as well as in vitro and in vivo vascular calcification models, and determined that soluble αKlotho specifically suppressed Hsp90aa1 activation-mediated osteogenic transdifferentiation of VSMCs and vascular calcification. The Hsp90aa1-specific inhibitor, 17-AAG, acted as an efficient therapeutic approach to attenuate vascular calcification in vivo and in vitro. Moreover, we revealed that the phosphorylation of Hsp90aa1 at Thr5/7 modulated its chaperone activity to stabilize Hif1α, thereby playing a causative role in the pathogenesis of vascular calcification. Upregulation of soluble αKlotho expression in VSMCs enhanced the interaction with Hsp90aa1 and blunted the phosphorylation of Hsp90aa1 at Thr5/7, which abolished Hsp90aa1-Hif1α axis activation in response to osteogenic induction. Our findings revealed a crucial pathway that soluble αKlotho interacts with Hsp90aa1 and suppresses the activation of the Hsp90aa1-Hif1α axis, which is involved in the osteogenic transdifferentiation of VSMCs and vascular calcification. Targeting Hsp90 may be a promising strategy for vascular calcification treatment, as various HSP90 inhibitors have been used for a range of clinical conditions.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 100-116"},"PeriodicalIF":4.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-05DOI: 10.1016/j.yjmcc.2025.06.013
David Chen , Andrew Sindone , Michael L.H. Huang , Karlheinz Peter , Alicia J. Jenkins
Diabetes mellitus is associated with significant morbidity and premature mortality for which heart failure (HF) is a major cause. HF may be due to ischaemia, hypertension, valvular disease, uraemia, or a specific diabetic cardiomyopathy, and multiple causes may co-exist. A recent systematic review suggests that >40 % of people with type 2 diabetes have diastolic dysfunction without a reduction of cardiac systolic function. In people with type 1 diabetes without known cardiovascular disease, 16 % had systolic or diastolic dysfunction. Early diabetic cardiomyopathy is asymptomatic and can progress to symptomatic HF via increasing cardiomyocyte hypertrophy and death as well as cardiac fibrosis. The 5-year mortality rate for HF is similar or worse than many common cancers. There have been significant recent advances in HF treatment including sodium-glucose co-transport 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi), and promising therapies such as finerenone and glucagon-like peptide-1 receptor agonists (GLP-1RA). SGLT2i, finerenone, and GLP-1RA may also have a role in HF prevention in asymptomatic diabetic cardiomyopathy. While there is currently no specific treatment for diabetic cardiomyopathy that goes beyond general HF treatment, there is promising research into innovative technologies such as gene and stem cell therapies. Also, digital technologies will likely have an increasing role in diabetic cardiomyopathy treatment. Herein we review the pathophysiology, diagnosis, and treatment of diabetic cardiomyopathy, with a focus on existing, emerging, and potentially promising novel therapies. We provide practical tables that summarise treatments at each stage as well as important practice points for commonly prescribed drugs.
{"title":"Diabetic cardiomyopathy: insights into pathophysiology, diagnosis and clinical management","authors":"David Chen , Andrew Sindone , Michael L.H. Huang , Karlheinz Peter , Alicia J. Jenkins","doi":"10.1016/j.yjmcc.2025.06.013","DOIUrl":"10.1016/j.yjmcc.2025.06.013","url":null,"abstract":"<div><div>Diabetes mellitus is associated with significant morbidity and premature mortality for which heart failure (HF) is a major cause. HF may be due to ischaemia, hypertension, valvular disease, uraemia, or a specific diabetic cardiomyopathy, and multiple causes may co-exist. A recent systematic review suggests that >40 % of people with type 2 diabetes have diastolic dysfunction without a reduction of cardiac systolic function. In people with type 1 diabetes without known cardiovascular disease, 16 % had systolic or diastolic dysfunction. Early diabetic cardiomyopathy is asymptomatic and can progress to symptomatic HF via increasing cardiomyocyte hypertrophy and death as well as cardiac fibrosis. The 5-year mortality rate for HF is similar or worse than many common cancers. There have been significant recent advances in HF treatment including sodium-glucose co-transport 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi), and promising therapies such as finerenone and glucagon-like peptide-1 receptor agonists (GLP-1RA). SGLT2i, finerenone, and GLP-1RA may also have a role in HF prevention in asymptomatic diabetic cardiomyopathy. While there is currently no specific treatment for diabetic cardiomyopathy that goes beyond general HF treatment, there is promising research into innovative technologies such as gene and stem cell therapies. Also, digital technologies will likely have an increasing role in diabetic cardiomyopathy treatment. Herein we review the pathophysiology, diagnosis, and treatment of diabetic cardiomyopathy, with a focus on existing, emerging, and potentially promising novel therapies. We provide practical tables that summarise treatments at each stage as well as important practice points for commonly prescribed drugs.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 55-69"},"PeriodicalIF":4.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vascular calcification is a common pathological feature of atherosclerosis, chronic kidney disease, vascular injury and aging. Human antigen R (HuR), a widely expressed RNA-binding protein, plays a key role in the regulation of homeostasis and pathological conditions such as cancer and cardiovascular disease, but its role in vascular calcification remains unclear. In this study, we generated smooth muscle-specific HuR knockout (HuRSMKO) mice to investigate the function of HuR in vascular calcification. The HuR level increased under calcifying conditions, and high phosphate levels increased HuR expression via activating transcription factor 4 (ATF4). HuR overexpression exacerbated high phosphate-induced calcification, whereas HuR deficiency inhibited high phosphate-induced calcification in VSMCs. Smooth muscle-specific knockout of HuR protected against vascular calcification in vivo. Additionally, treatment with the HuR inhibitor CMLD-2 significantly attenuated calcification in mice. Mechanistically, HuR binds directly to Runt-related transcription factor 2 (Runx2) mRNA, increasing its stability and protein expression, which facilitates vascular calcification. These findings demonstrate that HuR plays a critical role in the regulation of vascular calcification through the posttranscriptional control of Runx2.
{"title":"Smooth muscle-specific HuR knockout attenuates vascular calcification","authors":"Ang Chen, Peidong Yuan, Yue Lu, Chang Ma, Fei Xue, Jianmin Yang, Yun Zhang, Wencheng Zhang","doi":"10.1016/j.yjmcc.2025.07.002","DOIUrl":"10.1016/j.yjmcc.2025.07.002","url":null,"abstract":"<div><div>Vascular calcification is a common pathological feature of atherosclerosis, chronic kidney disease, vascular injury and aging. Human antigen R (HuR), a widely expressed RNA-binding protein, plays a key role in the regulation of homeostasis and pathological conditions such as cancer and cardiovascular disease, but its role in vascular calcification remains unclear. In this study, we generated smooth muscle-specific HuR knockout (HuR<sup>SMKO</sup>) mice to investigate the function of HuR in vascular calcification. The HuR level increased under calcifying conditions, and high phosphate levels increased HuR expression via activating transcription factor 4 (ATF4). HuR overexpression exacerbated high phosphate-induced calcification, whereas HuR deficiency inhibited high phosphate-induced calcification in VSMCs. Smooth muscle-specific knockout of HuR protected against vascular calcification in vivo. Additionally, treatment with the HuR inhibitor CMLD-2 significantly attenuated calcification in mice. Mechanistically, HuR binds directly to Runt-related transcription factor 2 (Runx2) mRNA, increasing its stability and protein expression, which facilitates vascular calcification. These findings demonstrate that HuR plays a critical role in the regulation of vascular calcification through the posttranscriptional control of Runx2.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 117-128"},"PeriodicalIF":4.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-04DOI: 10.1016/j.yjmcc.2025.06.010
Adnan Shaaban , Shane S. Scott , Ashley N. Greenlee , Nkongho Binda , Noor Ali , Averie Webb , Shuliang Guo , Najhee Purdy , Nicholas Pennza , Alma Habib , Somayya J. Mohammad , Sakima A. Smith
{"title":"Corrigendum to “Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms” [Journal of Molecular and Cellular Cardiology. 194 (2024): 118–132]","authors":"Adnan Shaaban , Shane S. Scott , Ashley N. Greenlee , Nkongho Binda , Noor Ali , Averie Webb , Shuliang Guo , Najhee Purdy , Nicholas Pennza , Alma Habib , Somayya J. Mohammad , Sakima A. Smith","doi":"10.1016/j.yjmcc.2025.06.010","DOIUrl":"10.1016/j.yjmcc.2025.06.010","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Page 99"},"PeriodicalIF":4.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.yjmcc.2025.06.012
Michaeljohn Kalakoutis , Yanhong Wang , Emma Smith , Alice Arcidiacono , Cameron Hill , Samina Juma , Atsuki Fukutani , Elisabetta Brunello , Luca Fusi , Malcolm Irving
Contraction of the muscular walls of the heart is driven by an interaction between myosin motors from the thick filaments and actin sites in the thin filaments. Each heartbeat is triggered by calcium binding to troponin in the thin filaments, which unblocks the myosin-binding sites on actin. The strength and speed of contraction is also modulated by the availability of myosin motors, which are sequestered in a helical array on the surface of the thick filaments between heartbeats. The signalling pathway controlling release of the motors from this array during the heartbeat is unknown, but there are three general hypotheses: thick-filament mechano-sensing, thin-to-thick filament signalling, and direct calcium signalling to the thick filament. Here we tested the third hypothesis by replacing the native calcium-binding subunit of troponin (TnC) with a variant which cannot bind calcium. Demembranated trabeculae from rat heart containing this variant generated no active force on addition of calcium. We measured calcium-induced release of myosin motors from the sequestered state by X-ray diffraction and from the orientation of fluorescent probes on the myosin regulatory light chain. Both methods showed the expected calcium-dependent changes in the conformation of the myosin motors in trabeculae containing native TnC, but all these changes were abolished in those containing the TnC variant that cannot bind calcium. We conclude that thick filament activation in rat heart trabeculae is not due to direct binding of calcium to thick filaments, but is mediated by calcium activation of the thin filaments by mechano-sensing or thin-to-thick filament signalling.
{"title":"Calcium binding to troponin C is required for activation of the myosin-containing thick filaments in rat cardiac trabeculae","authors":"Michaeljohn Kalakoutis , Yanhong Wang , Emma Smith , Alice Arcidiacono , Cameron Hill , Samina Juma , Atsuki Fukutani , Elisabetta Brunello , Luca Fusi , Malcolm Irving","doi":"10.1016/j.yjmcc.2025.06.012","DOIUrl":"10.1016/j.yjmcc.2025.06.012","url":null,"abstract":"<div><div>Contraction of the muscular walls of the heart is driven by an interaction between myosin motors from the thick filaments and actin sites in the thin filaments. Each heartbeat is triggered by calcium binding to troponin in the thin filaments, which unblocks the myosin-binding sites on actin. The strength and speed of contraction is also modulated by the availability of myosin motors, which are sequestered in a helical array on the surface of the thick filaments between heartbeats. The signalling pathway controlling release of the motors from this array during the heartbeat is unknown, but there are three general hypotheses: thick-filament mechano-sensing, thin-to-thick filament signalling, and direct calcium signalling to the thick filament. Here we tested the third hypothesis by replacing the native calcium-binding subunit of troponin (TnC) with a variant which cannot bind calcium. Demembranated trabeculae from rat heart containing this variant generated no active force on addition of calcium. We measured calcium-induced release of myosin motors from the sequestered state by X-ray diffraction and from the orientation of fluorescent probes on the myosin regulatory light chain. Both methods showed the expected calcium-dependent changes in the conformation of the myosin motors in trabeculae containing native TnC, but all these changes were abolished in those containing the TnC variant that cannot bind calcium. We conclude that thick filament activation in rat heart trabeculae is not due to direct binding of calcium to thick filaments, but is mediated by calcium activation of the thin filaments by mechano-sensing or thin-to-thick filament signalling.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 129-138"},"PeriodicalIF":4.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-30DOI: 10.1016/j.yjmcc.2025.06.011
Deng-Ren Ji , Rui Chang , Shi-Meng Liu , Ya-Rong Zhang , Jie Zhao , Yan-Rong Yu , Mo-Zhi Jia , Ning Wu , Hui-Fang Tang , Chao-Shu Tang , Ye-Bo Zhou , Yong-Fen Qi
The aging-associated cardiac remodeling (AACR) is characterized by myocardial hypertrophy, fibrosis and cardiac dysfunction, which could be further aggravated by angiotensin II (Ang II) and pressure-overload in aged people. In this study, we aimed to investigate the roles and mechanisms of intermedin1–53 (IMD1–53), an endogenous peptide, in AACR in aged mice (18 months) with subcutaneous Ang II infusion (1000 ng/kg/min) for 2 weeks via osmotic pump or transverse abdominal aorta constriction (AAC) surgery for 4 weeks. In aged mice undergoing Ang II infusion or AAC surgery, the results showed that the mRNA and protein levels of IMD1–53 were significantly reduced, but the protein levels of its receptor complex components were increased; blood pressure (BP), myocardial hypertrophy, fibrosis, and cardiac dysfunction were notably aggravated; mitochondrial Sirtuin 3 (SIRT3) protein level, superoxide dismutase 2 (SOD2) activity and ATP production were remarkably decreased, but acetylated SOD2 (acSOD2) protein level was markedly increased when compared with the old mice. The above alterations could be effectively alleviated by the subcutaneous IMD1–53 administration (5 ng/kg/min) for 2 or 4 weeks. In Ang II-stimulated cardiomyocytes, IMD1–53 treatment improved Ang II-induced mitochondrial dysfunction and oxidative distress, up-regulated SIRT3 protein expression, and reduced acSOD2 protein level, which were notably weakened by SIRT3 knockdown. Moreover, SIRT3 deletion attenuated the protective effects of IMD1–53 on myocardial hypertrophy, fibrosis, and cardiac dysfunction in aged mice undergoing Ang II infusion. In addition, the effect of IMD1–53 on up-regulating SIRT3 expression was effectively inhibited by the antagonism of IMD1–53 receptor or blocking PI3K/Akt, cAMP/PKA and AMPK signaling pathways in vitro. Taken together, IMD1–53 alleviated AACR and cardiac dysfunction aggravated by Ang II or pressure-overload involving the improvement of mitochondrial oxidative distress through SIRT3-medaiated SOD2 deacetylation.
{"title":"Intermedin1–53 improves aging-associated cardiac remodeling and dysfunction via mitochondrial SIRT3-mediated SOD2 deacetylation","authors":"Deng-Ren Ji , Rui Chang , Shi-Meng Liu , Ya-Rong Zhang , Jie Zhao , Yan-Rong Yu , Mo-Zhi Jia , Ning Wu , Hui-Fang Tang , Chao-Shu Tang , Ye-Bo Zhou , Yong-Fen Qi","doi":"10.1016/j.yjmcc.2025.06.011","DOIUrl":"10.1016/j.yjmcc.2025.06.011","url":null,"abstract":"<div><div>The aging-associated cardiac remodeling (AACR) is characterized by myocardial hypertrophy, fibrosis and cardiac dysfunction, which could be further aggravated by angiotensin II (Ang II) and pressure-overload in aged people. In this study, we aimed to investigate the roles and mechanisms of intermedin<sub>1</sub><sub>–</sub><sub>53</sub> (IMD<sub>1</sub><sub>–</sub><sub>53</sub>), an endogenous peptide, in AACR in aged mice (18 months) with subcutaneous Ang II infusion (1000 ng/kg/min) for 2 weeks via osmotic pump or transverse abdominal aorta constriction (AAC) surgery for 4 weeks. In aged mice undergoing Ang II infusion or AAC surgery, the results showed that the mRNA and protein levels of IMD<sub>1</sub><sub>–</sub><sub>53</sub> were significantly reduced, but the protein levels of its receptor complex components were increased; blood pressure (BP), myocardial hypertrophy, fibrosis, and cardiac dysfunction were notably aggravated; mitochondrial Sirtuin 3 (SIRT3) protein level, superoxide dismutase 2 (SOD2) activity and ATP production were remarkably decreased, but acetylated SOD2 (acSOD2) protein level was markedly increased when compared with the old mice. The above alterations could be effectively alleviated by the subcutaneous IMD<sub>1</sub><sub>–</sub><sub>53</sub> administration (5 ng/kg/min) for 2 or 4 weeks. In Ang II-stimulated cardiomyocytes, IMD<sub>1</sub><sub>–</sub><sub>53</sub> treatment improved Ang II-induced mitochondrial dysfunction and oxidative distress, up-regulated SIRT3 protein expression, and reduced acSOD2 protein level, which were notably weakened by SIRT3 knockdown. Moreover, SIRT3 deletion attenuated the protective effects of IMD<sub>1</sub><sub>–</sub><sub>53</sub> on myocardial hypertrophy, fibrosis, and cardiac dysfunction in aged mice undergoing Ang II infusion. In addition, the effect of IMD<sub>1</sub><sub>–</sub><sub>53</sub> on up-regulating SIRT3 expression was effectively inhibited by the antagonism of IMD<sub>1</sub><sub>–</sub><sub>53</sub> receptor or blocking PI3K/Akt, cAMP/PKA and AMPK signaling pathways in vitro. Taken together, IMD<sub>1</sub><sub>–</sub><sub>53</sub> alleviated AACR and cardiac dysfunction aggravated by Ang II or pressure-overload involving the improvement of mitochondrial oxidative distress through SIRT3-medaiated SOD2 deacetylation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"205 ","pages":"Pages 86-98"},"PeriodicalIF":4.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号