Pub Date : 2025-08-17DOI: 10.1016/j.yjmcc.2025.08.004
Shah R. Ali , Ngoc Uyen Nhi Nguyen , Waleed Elhelaly , Ching-Cheng Hsu , Shujuan Li , Ivan Menendez-Montes , Zhaoning Wang , Miao Cui , Abdallah Elnwasany , Feng Xiao , Jisheng Sun , Suwannee Thet , Nicholas T. Lam , Alisson Cardoso , Ana Helena Pereira , Jinhu Wang , Eric N. Olson , Michael T. Kinter , Luke I. Szweda , John Shelton , Hesham A. Sadek
We hypothesized that the microenvironment of the regenerating neonatal mouse heart contains pro-mitotic factors. To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating hearts for differentially expressed secreted proteins. We identified IGFBP3 in this screen as a neonatal injury-associated secreted protein. IGFBP3 belongs to a family of proteins that can stabilize and sequester IGF growth factors, as well as exert IGF-independent functions. In the neonatal heart, IGFBP3 is expressed and secreted predominantly by endothelial cells following injury, notably in the border zone of the infarct. We generated loss-of-function and gain-of-function mouse models to dissect the role of IGFBP3 in myocardial regeneration. Global deletion of Igfbp3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 or a tissue-specific ectopic Igfbp3 mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the murine heart. The temporal and spatial expression of an IGFBP3 protease (PAPPA2) and IGFBP3 in the infarct zone suggests that IGFBP3 proteolysis is coordinated to locally release IGF2, which can activate an Insulin/IGF-based growth pathway to stimulate cardiomyocyte division. Collectively, our work illuminates an endothelial-cardiomyocyte crosstalk involving IGFBP3 that can mediate myocardial regeneration in the neonatal heart.
{"title":"Paracrine IGFBP3 spatially coordinates IGF signaling to induce myocardial regeneration in mice","authors":"Shah R. Ali , Ngoc Uyen Nhi Nguyen , Waleed Elhelaly , Ching-Cheng Hsu , Shujuan Li , Ivan Menendez-Montes , Zhaoning Wang , Miao Cui , Abdallah Elnwasany , Feng Xiao , Jisheng Sun , Suwannee Thet , Nicholas T. Lam , Alisson Cardoso , Ana Helena Pereira , Jinhu Wang , Eric N. Olson , Michael T. Kinter , Luke I. Szweda , John Shelton , Hesham A. Sadek","doi":"10.1016/j.yjmcc.2025.08.004","DOIUrl":"10.1016/j.yjmcc.2025.08.004","url":null,"abstract":"<div><div>We hypothesized that the microenvironment of the regenerating neonatal mouse heart contains pro-mitotic factors. To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating hearts for differentially expressed secreted proteins. We identified IGFBP3 in this screen as a neonatal injury-associated secreted protein. IGFBP3 belongs to a family of proteins that can stabilize and sequester IGF growth factors, as well as exert IGF-independent functions. In the neonatal heart, IGFBP3 is expressed and secreted predominantly by endothelial cells following injury, notably in the border zone of the infarct. We generated loss-of-function and gain-of-function mouse models to dissect the role of IGFBP3 in myocardial regeneration. Global deletion of Igfbp3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 or a tissue-specific ectopic Igfbp3 mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the murine heart. The temporal and spatial expression of an IGFBP3 protease (PAPPA2) and IGFBP3 in the infarct zone suggests that IGFBP3 proteolysis is coordinated to locally release IGF2, which can activate an Insulin/IGF-based growth pathway to stimulate cardiomyocyte division. Collectively, our work illuminates an endothelial-cardiomyocyte crosstalk involving IGFBP3 that can mediate myocardial regeneration in the neonatal heart.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 93-106"},"PeriodicalIF":4.7,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883037","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 : 2025-08-15DOI: 10.1016/j.yjmcc.2025.08.003
Jin Guan, Dominic P. Del Re
The Hippo-YAP pathway is an evolutionarily conserved signaling module that regulates cell survival, proliferation, and differentiation to control organ size. Recent work has demonstrated critical roles for Hippo-YAP signaling in cardiac development and disease, including its ability to modulate both pathological and regenerative responses in the heart. Therefore, targeting the Hippo-YAP pathway for therapeutic benefit has gained attention and holds substantial promise for improving outcomes in patients with heart disease. Importantly, however, much of our understanding of cardiac Hippo-YAP signaling is based on studies in cardiomyocytes, and far less is known in other cell types in the heart. This review will focus primarily on the role of Hippo-YAP signaling in cardiomyocytes, cardiac fibroblasts, and macrophages, and explore how cell type-specific functions can impact heart development, as well as injury responses that can drive divergent outcomes in heart disease.
{"title":"Cell type specificity of Hippo-YAP signaling in cardiac development and disease","authors":"Jin Guan, Dominic P. Del Re","doi":"10.1016/j.yjmcc.2025.08.003","DOIUrl":"10.1016/j.yjmcc.2025.08.003","url":null,"abstract":"<div><div>The Hippo-YAP pathway is an evolutionarily conserved signaling module that regulates cell survival, proliferation, and differentiation to control organ size. Recent work has demonstrated critical roles for Hippo-YAP signaling in cardiac development and disease, including its ability to modulate both pathological and regenerative responses in the heart. Therefore, targeting the Hippo-YAP pathway for therapeutic benefit has gained attention and holds substantial promise for improving outcomes in patients with heart disease. Importantly, however, much of our understanding of cardiac Hippo-YAP signaling is based on studies in cardiomyocytes, and far less is known in other cell types in the heart. This review will focus primarily on the role of Hippo-YAP signaling in cardiomyocytes, cardiac fibroblasts, and macrophages, and explore how cell type-specific functions can impact heart development, as well as injury responses that can drive divergent outcomes in heart disease.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 51-63"},"PeriodicalIF":4.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867527","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 : 2025-08-09DOI: 10.1016/j.yjmcc.2025.08.001
Yanyan Zhou , Teng Yang , Suyang Zheng , Tiantian Gan , Fan Yu , Guizhu Liu , Tingting Zhou
Diabetic cardiomyopathy (DCM) is a serious complication associated with diabetes that characterized by the cardiac dysfunction and myocardial fibrosis. Recent studies emphasize the significance of the gut-heart axis in the development of DCM. This current study investigates the effect of systematic-genetical TRPV4 knockout on DCM progression and explores the underlying mechanisms involving gut microbiota modulation and intestinal barrier integrity. The removal of TRPV4 in mice with DCM markedly enhances cardiac performance, decreases myocardial fibrosis, and modifies the composition of gut microbiota, resulting in a significant rise in Bacteroides acidifaciens (BA). TRPV4 deletion also upregulates tight junction proteins (Zonula occludens-1 (ZO-1), Occludin, and Claudin-1) and reduces serum lipopolysaccharide levels. Furthermore, fecal microbiota transplantation from the DCM donors with TRPV4 knockout to the DCM receptors replicates these cardioprotective effects in mice, and administration of BA improves cardiac function and relieves the fibrosis. Our study suggests that the cardioprotective effects of the genetic deletion of TRPV4 are related to changes in the gut microbiome, highlighting the importance of the connection between TRPV4, the gut, and the heart in the disease mechanism and potential therapeutic strategies for DCM.
{"title":"Genetical TRPV4 deletion-associated gut microbiota alleviates cardiac dysfunction in mice with diabetic cardiomyopathy","authors":"Yanyan Zhou , Teng Yang , Suyang Zheng , Tiantian Gan , Fan Yu , Guizhu Liu , Tingting Zhou","doi":"10.1016/j.yjmcc.2025.08.001","DOIUrl":"10.1016/j.yjmcc.2025.08.001","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is a serious complication associated with diabetes that characterized by the cardiac dysfunction and myocardial fibrosis. Recent studies emphasize the significance of the gut-heart axis in the development of DCM. This current study investigates the effect of systematic-genetical TRPV4 knockout on DCM progression and explores the underlying mechanisms involving gut microbiota modulation and intestinal barrier integrity. The removal of TRPV4 in mice with DCM markedly enhances cardiac performance, decreases myocardial fibrosis, and modifies the composition of gut microbiota, resulting in a significant rise in <em>Bacteroides acidifaciens</em> (BA). TRPV4 deletion also upregulates tight junction proteins (Zonula occludens-1 (ZO-1), Occludin, and Claudin-1) and reduces serum lipopolysaccharide levels. Furthermore, fecal microbiota transplantation from the DCM donors with TRPV4 knockout to the DCM receptors replicates these cardioprotective effects in mice, and administration of BA improves cardiac function and relieves the fibrosis. Our study suggests that the cardioprotective effects of the genetic deletion of TRPV4 are related to changes in the gut microbiome, highlighting the importance of the connection between TRPV4, the gut, and the heart in the disease mechanism and potential therapeutic strategies for DCM.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 37-50"},"PeriodicalIF":4.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821605","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 : 2025-08-02DOI: 10.1016/j.yjmcc.2025.07.018
Shuyuan Sheng , Xianpeng Wu , Changchen Xiao , Jiamin Li , Changle Ke , Xinyang Hu , Cheng Ni
Background
Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent, but its clinical application is limited by severe side effects, particularly DOX-induced cardiomyopathy (DIC) which is closely associated with oxidative stress, DNA damage and, subsequent apoptosis. Flavin-containing monooxygenase 2 (FMO2), a cardiac-enriched enzyme, catalyzes NADPH-dependent oxidative metabolism of diverse pharmaceuticals. Our previous work demonstrated that FMO2 expression confers cardioprotective effects against ischemic cardiomyopathy; however, the role of FMO2 in DIC has not been demonstrated.
Methods
DIC was induced in wild-type, FMO2−/−, and cardiomyocyte-specific FMO2-overexpressing mice. Neonatal rat ventricular myocytes were assessed following adenoviral-mediated FMO2 knockdown or overexpression. Transcriptome profiling and chromatin analysis elucidated the mechanism involving FMO2-mediated attenuation of DOX-induced DNA damage. A xenograft model was used to evaluate the impact of FMO2 on DOX's antitumor efficacy.
Results
FMO2 expression was suppressed in heart following DIC. Genetic ablation of FMO2 exacerbated DIC, whereas cardiomyocyte-specific FMO2 overexpression mitigated DOX-induced cardiac injury. Mechanistically, FMO2 reduced DOX-induced DNA damage by stabilizing chromatin-associated X-ray repair cross-complementing protein 4-like factor (XLF), thereby promoting DNA repair. Furthermore, FMO2 expression did not compromise DOX's antitumor efficacy.
Conclusions
FMO2 expression confers cardiac protection against DIC by stabilizing chromatin-associated XLF to facilitate DNA repair. Critically, cardiac FMO2 expression preserves DOX's antitumor efficacy, establishing it as a potential target for DIC management.
{"title":"FMO2 expression confers cardioprotection in doxorubicin therapy while preserving antitumor activity","authors":"Shuyuan Sheng , Xianpeng Wu , Changchen Xiao , Jiamin Li , Changle Ke , Xinyang Hu , Cheng Ni","doi":"10.1016/j.yjmcc.2025.07.018","DOIUrl":"10.1016/j.yjmcc.2025.07.018","url":null,"abstract":"<div><h3>Background</h3><div>Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent, but its clinical application is limited by severe side effects, particularly DOX-induced cardiomyopathy (DIC) which is closely associated with oxidative stress, DNA damage and, subsequent apoptosis. Flavin-containing monooxygenase 2 (FMO2), a cardiac-enriched enzyme, catalyzes NADPH-dependent oxidative metabolism of diverse pharmaceuticals. Our previous work demonstrated that FMO2 expression confers cardioprotective effects against ischemic cardiomyopathy; however, the role of FMO2 in DIC has not been demonstrated.</div></div><div><h3>Methods</h3><div>DIC was induced in wild-type, FMO2<sup>−/−</sup>, and cardiomyocyte-specific FMO2-overexpressing mice. Neonatal rat ventricular myocytes were assessed following adenoviral-mediated FMO2 knockdown or overexpression. Transcriptome profiling and chromatin analysis elucidated the mechanism involving FMO2-mediated attenuation of DOX-induced DNA damage. A xenograft model was used to evaluate the impact of FMO2 on DOX's antitumor efficacy.</div></div><div><h3>Results</h3><div>FMO2 expression was suppressed in heart following DIC. Genetic ablation of FMO2 exacerbated DIC, whereas cardiomyocyte-specific FMO2 overexpression mitigated DOX-induced cardiac injury. Mechanistically, FMO2 reduced DOX-induced DNA damage by stabilizing chromatin-associated X-ray repair cross-complementing protein 4-like factor (XLF), thereby promoting DNA repair. Furthermore, FMO2 expression did not compromise DOX's antitumor efficacy.</div></div><div><h3>Conclusions</h3><div>FMO2 expression confers cardiac protection against DIC by stabilizing chromatin-associated XLF to facilitate DNA repair. Critically, cardiac FMO2 expression preserves DOX's antitumor efficacy, establishing it as a potential target for DIC management.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 1-12"},"PeriodicalIF":4.7,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144767043","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 : 2025-07-29DOI: 10.1016/j.yjmcc.2025.07.017
Arasakumar Subramani , Kobina Essandoh , Michael Y. Young , Francesca H. Marino , James P. Teuber , Kay-Uwe Wagner , Matthew J. Brody
Despite the essential role of inflammation in the pathogenesis of heart failure and other chronic cardiovascular diseases, how cardiomyocytes sense and respond to the inflammatory milieu is not well understood. Cytokine receptors respond to circulating glycoprotein 130 (gp130) family cytokines, such as interleukin-6 (IL-6) and oncostatin M (OSM), by signaling through Janus kinases (JAK) to ultimately elicit phosphorylation-dependent nuclear translocation and transcriptional activity of signal transducer and activator of transcription (STAT) proteins. JAK1 is particularly important for STAT3-dependent cytokine production and macrophage recruitment by cardiomyocytes and STAT3 promotes cardiac hypertrophy and remodeling in response to pressure overload or angiotensin-II but is protective during ischemic injury. However, the roles of JAK1 signaling in cardiac homeostasis and cardiomyocyte cytokine sensing and responsivity remain unclear. To assess the functions of JAK1 in cardiac physiology, we generated mice with cardiomyocyte-specific deletion of JAK1 and evaluated cardiac structure and function, myocardial remodeling, and intracellular signal transduction. Loss of JAK1 in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. Cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterized by substantial myocardial fibrosis. Transcriptomics and gene expression analyses identified JAK1-dependent cytokine-inducible target genes in adult cardiomyocytes as putative effectors of JAK1-STAT3 in the cardiac stress response. JAK1-deficient adult cardiomyocytes were resistant to phosphorylation and nuclear translocation of STAT3 and transcriptional reprogramming in response to OSM. Collectively these data indicate cardiomyocyte JAK1 kinase activity is required for proper cardiac maturation and homeostasis and is indispensable for STAT3 activation and transcriptional responses to OSM.
{"title":"Cardiomyocyte Janus kinase 1 (JAK1) signaling is required for cardiac homeostasis and cytokine-dependent activation of STAT3","authors":"Arasakumar Subramani , Kobina Essandoh , Michael Y. Young , Francesca H. Marino , James P. Teuber , Kay-Uwe Wagner , Matthew J. Brody","doi":"10.1016/j.yjmcc.2025.07.017","DOIUrl":"10.1016/j.yjmcc.2025.07.017","url":null,"abstract":"<div><div>Despite the essential role of inflammation in the pathogenesis of heart failure and other chronic cardiovascular diseases, how cardiomyocytes sense and respond to the inflammatory milieu is not well understood. Cytokine receptors respond to circulating glycoprotein 130 (gp130) family cytokines, such as interleukin-6 (IL-6) and oncostatin M (OSM), by signaling through Janus kinases (JAK) to ultimately elicit phosphorylation-dependent nuclear translocation and transcriptional activity of signal transducer and activator of transcription (STAT) proteins. JAK1 is particularly important for STAT3-dependent cytokine production and macrophage recruitment by cardiomyocytes and STAT3 promotes cardiac hypertrophy and remodeling in response to pressure overload or angiotensin-II but is protective during ischemic injury. However, the roles of JAK1 signaling in cardiac homeostasis and cardiomyocyte cytokine sensing and responsivity remain unclear. To assess the functions of JAK1 in cardiac physiology, we generated mice with cardiomyocyte-specific deletion of JAK1 and evaluated cardiac structure and function, myocardial remodeling, and intracellular signal transduction. Loss of JAK1 in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. Cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterized by substantial myocardial fibrosis. Transcriptomics and gene expression analyses identified JAK1-dependent cytokine-inducible target genes in adult cardiomyocytes as putative effectors of JAK1-STAT3 in the cardiac stress response. JAK1-deficient adult cardiomyocytes were resistant to phosphorylation and nuclear translocation of STAT3 and transcriptional reprogramming in response to OSM. Collectively these data indicate cardiomyocyte JAK1 kinase activity is required for proper cardiac maturation and homeostasis and is indispensable for STAT3 activation and transcriptional responses to OSM.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 13-23"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760276","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 : 2025-07-29DOI: 10.1016/j.yjmcc.2025.07.016
Haiwang Shi , Pengsheng Li , Hannah Prachyl, Rebecca Thomas, Ling Tang, Wuqiang Zhu
While circular RNAs (circRNAs) regulating angiogenesis have been identified in fish and rodent hearts, their expression profiles in pig hearts remain largely unknown. This study aims to identify circRNAs that regulate angiogenesis in postnatal pig hearts. Total RNA sequencing data on pig heart tissues collected on postnatal days 1 (P1), 3 (P3), 7 (P7) and 28 (P28) were previously reported. This study analyzed conserved circRNAs associated with angiogenesis in the database. Functional studies were conducted in human umbilical vein endothelial cells (HUVECs) and hiPSC-derived endothelial cells (hiPSC-ECs). siRNA-mediated knockdown of circRNAs and miRNAs was performed to validate their functions in regulating angiogenesis. Fluorescence in situ hybridization was used to examine circRNA localization. Sus-PSMB7_0001 expression increased in pig hearts at P7 and P28 compared to P1 and P3. Knockdown of hsa-PSMB7_0025 (the human orthologue of sus-PSMB7_0001) impaired DNA synthesis, mitosis, migration, and tube formation in HUVECs and hiPSC-ECs. hsa-PSMB7_0025 negatively regulated hsa-miR-490-3p. Activation of hsa-miR-490-3p inhibited hiPSC-EC proliferation, while its inhibition promoted proliferation. Inhibition of miR-490-3p upregulated hsa-PSMB7_0025. miR-490-3p regulates five downstream effectors (TP53BP1, TMOD3, CDYL2, FOXO1, and TGFBR1) involved in cell cycle and vascular function. These findings suggest circRNA sus-PSMB7_0001 is a potential pro-angiogenic molecule in neonatal pig hearts.
{"title":"Identification of sus-PSMB7_0001 as a potential pro-angiogenic circular RNA in neonatal pig hearts","authors":"Haiwang Shi , Pengsheng Li , Hannah Prachyl, Rebecca Thomas, Ling Tang, Wuqiang Zhu","doi":"10.1016/j.yjmcc.2025.07.016","DOIUrl":"10.1016/j.yjmcc.2025.07.016","url":null,"abstract":"<div><div>While circular RNAs (circRNAs) regulating angiogenesis have been identified in fish and rodent hearts, their expression profiles in pig hearts remain largely unknown. This study aims to identify circRNAs that regulate angiogenesis in postnatal pig hearts. Total RNA sequencing data on pig heart tissues collected on postnatal days 1 (P1), 3 (P3), 7 (P7) and 28 (P28) were previously reported. This study analyzed conserved circRNAs associated with angiogenesis in the database. Functional studies were conducted in human umbilical vein endothelial cells (HUVECs) and hiPSC-derived endothelial cells (hiPSC-ECs). siRNA-mediated knockdown of circRNAs and miRNAs was performed to validate their functions in regulating angiogenesis. Fluorescence in situ hybridization was used to examine circRNA localization. Sus-PSMB7_0001 expression increased in pig hearts at P7 and P28 compared to P1 and P3. Knockdown of hsa-PSMB7_0025 (the human orthologue of sus-PSMB7_0001) impaired DNA synthesis, mitosis, migration, and tube formation in HUVECs and hiPSC-ECs. hsa-PSMB7_0025 negatively regulated hsa-miR-490-3p. Activation of hsa-miR-490-3p inhibited hiPSC-EC proliferation, while its inhibition promoted proliferation. Inhibition of miR-490-3p upregulated hsa-PSMB7_0025. miR-490-3p regulates five downstream effectors (TP53BP1, TMOD3, CDYL2, FOXO1, and TGFBR1) involved in cell cycle and vascular function. These findings suggest circRNA sus-PSMB7_0001 is a potential pro-angiogenic molecule in neonatal pig hearts.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"207 ","pages":"Pages 24-36"},"PeriodicalIF":4.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760277","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 : 2025-07-25DOI: 10.1016/j.yjmcc.2025.07.001
Sebastiaan Lootens , Robin Van Den Abeele , Vineesh Kappadan , Balvinder Handa , Matthias Duytschaever , Sebastien Knecht , Armin Luik , Annika Haas , Eike M. Wülfers , Arthur Santos Bezerra , Bjorn Verstraeten , Sander Hendrickx , Arstanbek Okenov , Timur Nezlobinsky , Fu Siong Ng , Nele Vandersickel
{"title":"Corrigendum to “Detection of regular rotational activity during cardiac arrhythmia using the Helmholtz decomposition for directed graphs.” [Journal of Molecular and Cellular Cardiology 204 (2025) p40–54]","authors":"Sebastiaan Lootens , Robin Van Den Abeele , Vineesh Kappadan , Balvinder Handa , Matthias Duytschaever , Sebastien Knecht , Armin Luik , Annika Haas , Eike M. Wülfers , Arthur Santos Bezerra , Bjorn Verstraeten , Sander Hendrickx , Arstanbek Okenov , Timur Nezlobinsky , Fu Siong Ng , Nele Vandersickel","doi":"10.1016/j.yjmcc.2025.07.001","DOIUrl":"10.1016/j.yjmcc.2025.07.001","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Page 113"},"PeriodicalIF":4.9,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703846","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 : 2025-07-24DOI: 10.1016/j.yjmcc.2025.07.014
Spyros Zissimopoulos , Pavel Kirilenko , Aitana Braza-Boïls , Esther Zorio , Yueyi Wang , Ana Maria Gomez , Mark B. Cannell , Branko Latinkic , Ewan D. Fowler
Background
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca2+ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca2+ leak during systole disrupts repolarization in a transgenic mouse model of CPVT.
Methods
Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.
Results
R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca2+ leak during the Ca2+ transient decay, in the form of late Ca2+ sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.
Conclusions
Ca2+-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.
{"title":"Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation","authors":"Spyros Zissimopoulos , Pavel Kirilenko , Aitana Braza-Boïls , Esther Zorio , Yueyi Wang , Ana Maria Gomez , Mark B. Cannell , Branko Latinkic , Ewan D. Fowler","doi":"10.1016/j.yjmcc.2025.07.014","DOIUrl":"10.1016/j.yjmcc.2025.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca<sup>2+</sup> cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca<sup>2+</sup> leak during systole disrupts repolarization in a transgenic mouse model of CPVT.</div></div><div><h3>Methods</h3><div>Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.</div></div><div><h3>Results</h3><div>R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca<sup>2+</sup> leak during the Ca<sup>2+</sup> transient decay, in the form of late Ca<sup>2+</sup> sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.</div></div><div><h3>Conclusions</h3><div>Ca<sup>2+</sup>-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 127-140"},"PeriodicalIF":4.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717966","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 : 2025-07-23DOI: 10.1016/j.yjmcc.2025.07.015
Dongqing Chen , Amanda J. Croft , Tatt Jhong Haw , Conagh Kelly , Lohis Balachandran , Aaron L. Sverdlov , Doan T.M. Ngo
Inhibition of poly (ADP-ribose) polymerase (PARP) has shown cardioprotective effects in myocardial injury, and PARP activation has been implicated in Doxorubicin-induced cardiotoxicity (DIC). Thus, PARP inhibition may be a potential preventive therapy for DIC. The present study aims to determine the cardioprotective effects of Olaparib in preventing DIC in in vitro and in vivo models. In vitro: Human cardiomyocytes (HCM) were treated with Doxorubicin at 1 μM (EC50) +/− 80 μM of Olaparib for 48 and 72 h, assessing cell viability (CellTiter-Glo®) and conducted gene expression analysis; Concomitant Olaparib treatment prevented Doxorubicin-induced impairment of HCM viability. Doxorubicin induced upregulation of mRNA expressions of genes involved in apoptosis: CASP3; DNA damage: BBC3; and cardiac remodeling: TGF-β; −all were reversed by Olaparib. In vivo: Female C57BL/6 mice were administered intraperitoneally either: A) vehicle of 0.9 % saline and 8 % DMSO in PBS; B) Doxorubicin at 5 mg/kg/wk. for 5 weeks; C) Olaparib at a dose of 50 mg/kg in 8 % DMSO, administered 3 times/week; D) Olaparib at 50 mg/kg, administered 3 times/week, started one week prior to commencement of Doxorubicin treatments at 5 mg/kg/week. Serial echocardiography was performed. mRNA, protein expressions and RNA sequencing were performed in the cardiac tissues; Doxorubicin induced significant LV dysfunction after 6 weeks of treatment; whereas the mice treated with Olaparib in combination with Doxorubicin showed preservation of cardiac function. Analysis of RNA-seq and Western blot data suggested that Olaparib's cardioprotective effects in DIC may involve regulating innate immune responses by lowering cGAS-STING levels, elevated by Doxorubicin. Olaparib protects HCM against DIC both in vitro and in vivo. This is mediated in part via cGAS-STING pathway.
{"title":"Anti-cancer agent Olaparib ameliorates doxorubicin-induced cardiotoxicity in vitro and in vivo","authors":"Dongqing Chen , Amanda J. Croft , Tatt Jhong Haw , Conagh Kelly , Lohis Balachandran , Aaron L. Sverdlov , Doan T.M. Ngo","doi":"10.1016/j.yjmcc.2025.07.015","DOIUrl":"10.1016/j.yjmcc.2025.07.015","url":null,"abstract":"<div><div>Inhibition of poly (ADP-ribose) polymerase (PARP) has shown cardioprotective effects in myocardial injury, and PARP activation has been implicated in Doxorubicin-induced cardiotoxicity (DIC). Thus, PARP inhibition may be a potential preventive therapy for DIC. The present study aims to determine the cardioprotective effects of Olaparib in preventing DIC in in vitro and in vivo models. In vitro<em>:</em> Human cardiomyocytes (HCM) were treated with Doxorubicin at 1 μM (EC50) +/− 80 μM of Olaparib for 48 and 72 h, assessing cell viability (CellTiter-Glo®) and conducted gene expression analysis; Concomitant Olaparib treatment prevented Doxorubicin-induced impairment of HCM viability. Doxorubicin induced upregulation of mRNA expressions of genes involved in apoptosis: <em>CASP3</em>; DNA damage: <em>BBC3</em>; and cardiac remodeling: <em>TGF-β</em>; −all were reversed by Olaparib. In vivo<em>:</em> Female C57BL/6 mice were administered intraperitoneally either: A) vehicle of 0.9 % saline and 8 % DMSO in PBS; B) Doxorubicin at 5 mg/kg/wk. for 5 weeks; C) Olaparib at a dose of 50 mg/kg in 8 % DMSO, administered 3 times/week; D) Olaparib at 50 mg/kg, administered 3 times/week, started one week prior to commencement of Doxorubicin treatments at 5 mg/kg/week. Serial echocardiography was performed. mRNA, protein expressions and RNA sequencing were performed in the cardiac tissues; Doxorubicin induced significant LV dysfunction after 6 weeks of treatment; whereas the mice treated with Olaparib in combination with Doxorubicin showed preservation of cardiac function. Analysis of RNA-seq and Western blot data suggested that Olaparib's cardioprotective effects in DIC may involve regulating innate immune responses by lowering cGAS-STING levels, elevated by Doxorubicin. Olaparib protects HCM against DIC both in vitro and in vivo. This is mediated in part via cGAS-STING pathway.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 114-126"},"PeriodicalIF":4.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713407","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 : 2025-07-17DOI: 10.1016/j.yjmcc.2025.07.013
E.V. Minnebaeva , M.A. Gonotkov , A.V. Durkina , E.A. Lebedeva , A.V. Fedorov , M.A. Chelombitko , O.B. Pustovit , T.S. Filatova , J.E. Azarov , O.G. Bernikova
Introduction
The aging myocardium undergoes significant electrophysiological and structural remodeling. These complex alterations may affect conduction velocity (CV), whose age-related changes remain unclear. This study aims at evaluation of the CV changes in the rats of different ages and assessment of the contribution of cellular and tissue factors into CV.
Methods
The CV was determined in 3-, 12- and 24-month-old anesthetized rats using epicardial mapping under ventricular stimulation. The contribution of gap junction functionality to CV was assessed using carbenoxolone, an uncoupling agent for Cx43. The measurement of sodium ion current (INa) was performed in isolated ventricular cardiomyocytes using the patch-clamp technique. Expression of gene transcripts encoding Cx43 (GJA1a) and sodium currents (SCN5a) were assessed using RT-PCR analysis.
Results
The baseline longitudinal conduction velocity (CVL) did not differ between 3-, 12- and 24-month-old groups. Intravenous administration of carbenoxolone decreased the CVL only in the 3-month-old animals. The density of sodium current (INa) of 24-month-old rats was greater as compared to 3-month-old rats. The extent of fibrosis was less prominent in 3-month-old rats than in the older animals. The expression of SCN5a gene transcripts was increased and expression of GJA1a was decreased in the 24-month-old rats.
Conclusions
The enhancement of sodium current preserves conduction velocity despite impaired connexin function and increased fibrosis in the aging myocardium.
{"title":"Enhancement of sodium current contributes to the maintenance of conduction velocity in the aging myocardium","authors":"E.V. Minnebaeva , M.A. Gonotkov , A.V. Durkina , E.A. Lebedeva , A.V. Fedorov , M.A. Chelombitko , O.B. Pustovit , T.S. Filatova , J.E. Azarov , O.G. Bernikova","doi":"10.1016/j.yjmcc.2025.07.013","DOIUrl":"10.1016/j.yjmcc.2025.07.013","url":null,"abstract":"<div><h3>Introduction</h3><div>The aging myocardium undergoes significant electrophysiological and structural remodeling. These complex alterations may affect conduction velocity (CV), whose age-related changes remain unclear. This study aims at evaluation of the CV changes in the rats of different ages and assessment of the contribution of cellular and tissue factors into CV.</div></div><div><h3>Methods</h3><div>The CV was determined in 3-, 12- and 24-month-old anesthetized rats using epicardial mapping under ventricular stimulation. The contribution of gap junction functionality to CV was assessed using carbenoxolone, an uncoupling agent for Cx43. The measurement of sodium ion current (I<sub>Na</sub>) was performed in isolated ventricular cardiomyocytes using the patch-clamp technique. Expression of gene transcripts encoding Cx43 (GJA1a) and sodium currents (SCN5a) were assessed using RT-PCR analysis.</div></div><div><h3>Results</h3><div>The baseline longitudinal conduction velocity (CV<sub>L</sub>) did not differ between 3-, 12- and 24-month-old groups. Intravenous administration of carbenoxolone decreased the CV<sub>L</sub> only in the 3-month-old animals. The density of sodium current (I<sub>Na</sub>) of 24-month-old rats was greater as compared to 3-month-old rats. The extent of fibrosis was less prominent in 3-month-old rats than in the older animals. The expression of SCN5a gene transcripts was increased and expression of GJA1a was decreased in the 24-month-old rats.</div></div><div><h3>Conclusions</h3><div>The enhancement of sodium current preserves conduction velocity despite impaired connexin function and increased fibrosis in the aging myocardium.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"206 ","pages":"Pages 102-112"},"PeriodicalIF":4.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667765","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}
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