The regulatory mechanisms for inflammatory response in the heart to endotoxin, which causes severe cardiac dysfunction, are not fully understood. We hypothesized the involvement of coxsackie and adenovirus receptor (CXADR), which can promote tissue inflammation by potentiating cell-cell adhesion, independent of viral infection, and examined the role of CXADR in endotoxin-induced cardiac dysfunction and its mechanism using an experimental mouse model. Conditional whole-body and endothelium-specific CXADR knockout (W-KO and E-KO, respectively) mice were generated using the Cre-loxP system and administered lipopolysaccharide (LPS) or vehicle alone, like wild-type (WT) mice. Cardiac CXADR increased 12 h after LPS challenge in WT mice, along with improved cardiac dysfunction and reduced cardiac expression of interleukin (IL)-6 and IL-1β. Moreover, W-KO in adult mice worsened cardiac dysfunction and increased expression of these cytokines. Meanwhile, E-KO exhibited the opposite effects, concomitantly reducing myocardial inflammation. Bulk RNA sequencing analysis identified an enriched IL-17 A signaling pathway capable of inducing IL-6 and IL-1β expression in the heart 12 h after LPS challenge. In this heart, E-KO attenuated phosphorylation of p38 but not of upstream mitogen-activated protein kinase kinase (MKK)3/6. Conversely, W-KO augmented phosphorylation of p38, MKK3/6, and NF-κB/p65, which are key drivers of the IL-17 A signaling. Our study is the first to demonstrate that increased CXADR expression plays a dual role as both a pro-inflammatory mediator and an anti-inflammatory protector in endotoxin-induced cardiac dysfunction, possibly by positively or negatively regulating p38 activation depending on its cellular origin. Targeted manipulation of CXADR expression may provide clinical benefits.
{"title":"Coxsackie and adenovirus receptor is a novel regulator of inflammatory response in endotoxin-induced failing heart.","authors":"Reo Matsumura , Mototsugu Nishii , Haruya Usuku , Masahiro Nakayama , Masaki Hachisuka , Naho Misawa , Ryo Saji , Fumihiro Ogawa , Alan Valaperti , Yoshihiro Ishikawa , Ichiro Takeuchi","doi":"10.1016/j.jmccpl.2025.100496","DOIUrl":"10.1016/j.jmccpl.2025.100496","url":null,"abstract":"<div><div>The regulatory mechanisms for inflammatory response in the heart to endotoxin, which causes severe cardiac dysfunction, are not fully understood. We hypothesized the involvement of coxsackie and adenovirus receptor (CXADR), which can promote tissue inflammation by potentiating cell-cell adhesion, independent of viral infection, and examined the role of CXADR in endotoxin-induced cardiac dysfunction and its mechanism using an experimental mouse model. Conditional whole-body and endothelium-specific CXADR knockout (W-KO and <em>E</em>-KO, respectively) mice were generated using the Cre-loxP system and administered lipopolysaccharide (LPS) or vehicle alone, like wild-type (WT) mice. Cardiac CXADR increased 12 h after LPS challenge in WT mice, along with improved cardiac dysfunction and reduced cardiac expression of interleukin (IL)-6 and IL-1β. Moreover, W-KO in adult mice worsened cardiac dysfunction and increased expression of these cytokines. Meanwhile, <em>E</em>-KO exhibited the opposite effects, concomitantly reducing myocardial inflammation. Bulk RNA sequencing analysis identified an enriched IL-17 A signaling pathway capable of inducing IL-6 and IL-1β expression in the heart 12 h after LPS challenge. In this heart, <em>E</em>-KO attenuated phosphorylation of p38 but not of upstream mitogen-activated protein kinase kinase (MKK)3/6. Conversely, W-KO augmented phosphorylation of p38, MKK3/6, and NF-κB/p65, which are key drivers of the IL-17 A signaling. Our study is the first to demonstrate that increased CXADR expression plays a dual role as both a pro-inflammatory mediator and an anti-inflammatory protector in endotoxin-induced cardiac dysfunction, possibly by positively or negatively regulating p38 activation depending on its cellular origin. Targeted manipulation of CXADR expression may provide clinical benefits.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100496"},"PeriodicalIF":2.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.jmccpl.2025.100495
Chad M. Warren , David M. Ryba , Gail E. Geist , Aileen Castro Coronado , Beata M. Wolska , Paul H. Goldspink , R. John Solaro
The disease-causing myosin variant (MYH7-403Q) is linked to hypertrophic cardiomyopathy (HCM). We carried out a research study of signaling pathways in heart samples from control wild-type (WT) GE Yucatán mini-pigs and their littermates harboring the gene variant, MYH7-R403Q. Our approach permits the determination of adverse signaling pathways involved in different regions of a translationally relevant heart without the effects of intervention. We examined the left ventricular free wall (LV), endocardium (EN), and coronary arteries (CA) from 5 transgenic and 5 wild-type mini-pig littermates to determine alterations in global phosphorylation and protein abundance. Digested peptides from 6 to 7 months old mixed-sex mini-pigs were isobarically labeled; 95 % were phospho-enriched, and 5 % were used as the unmodified (total) fraction. The phospho-enriched and unmodified fractions were injected into an Orbitrap Fusion Lumos and analyzed using PEAKS Studio and Ingenuity Pathway Analysis. Surprisingly, we found no significant changes in the phospho-peptide and unmodified protein abundances in CA. Compared to WT, both LV and EN samples displayed minor changes in phosphorylation and significant changes in unmodified proteins. Bioinformatic analysis revealed that pathways associated with mechano-signaling between cardiomyocytes and the extracellular matrix and inflammation were altered in LV and EN samples. In addition, EN samples had larger differences in pathways related to metabolic dysfunction compared to LV. Our findings provide a translational understanding of signaling pathways altered in the MYH7-R403Q gene variant.
引起疾病的肌球蛋白变体（MYH7-403Q）与肥厚性心肌病（HCM）有关。我们对携带MYH7-R403Q基因变体的对照野生型（WT） GE Yucatán迷你猪及其窝仔的心脏样本的信号通路进行了研究。我们的方法允许在没有干预影响的情况下确定涉及翻译相关心脏不同区域的不良信号通路。我们检测了5只转基因猪和5只野生型迷你猪的左心室游离壁（LV）、心内膜（EN）和冠状动脉（CA），以确定其整体磷酸化和蛋白质丰度的变化。对6 ~ 7月龄混合型小型猪的消化肽进行等压标记；95%是富磷的，5%是未修饰的（总）部分。将富磷和未修饰的部分注入Orbitrap Fusion Lumos，并使用PEAKS Studio和Ingenuity Pathway Analysis进行分析。令人惊讶的是，我们发现CA的磷酸化肽和未修饰蛋白丰度没有显著变化。与WT相比，LV和EN样品的磷酸化变化较小，未修饰蛋白的变化显著。生物信息学分析显示，在LV和EN样本中，心肌细胞与细胞外基质和炎症之间的机械信号通路发生了改变。此外，与LV相比，EN样本在与代谢功能障碍相关的途径上存在更大的差异。我们的研究结果提供了对MYH7-R403Q基因变异中信号通路改变的翻译理解。
{"title":"Signaling pathway alterations in hearts of a porcine model harboring a β-myosin heavy chain (MYH7-R403Q) gene variant","authors":"Chad M. Warren , David M. Ryba , Gail E. Geist , Aileen Castro Coronado , Beata M. Wolska , Paul H. Goldspink , R. John Solaro","doi":"10.1016/j.jmccpl.2025.100495","DOIUrl":"10.1016/j.jmccpl.2025.100495","url":null,"abstract":"<div><div>The disease-causing myosin variant (MYH7-403Q) is linked to hypertrophic cardiomyopathy (HCM). We carried out a research study of signaling pathways in heart samples from control wild-type (WT) GE Yucatán mini-pigs and their littermates harboring the gene variant, MYH7-R403Q. Our approach permits the determination of adverse signaling pathways involved in different regions of a translationally relevant heart without the effects of intervention. We examined the left ventricular free wall (LV), endocardium (EN), and coronary arteries (CA) from 5 transgenic and 5 wild-type mini-pig littermates to determine alterations in global phosphorylation and protein abundance. Digested peptides from 6 to 7 months old mixed-sex mini-pigs were isobarically labeled; 95 % were phospho-enriched, and 5 % were used as the unmodified (total) fraction. The phospho-enriched and unmodified fractions were injected into an Orbitrap Fusion Lumos and analyzed using PEAKS Studio and Ingenuity Pathway Analysis. Surprisingly, we found no significant changes in the phospho-peptide and unmodified protein abundances in CA. Compared to WT, both LV and EN samples displayed minor changes in phosphorylation and significant changes in unmodified proteins. Bioinformatic analysis revealed that pathways associated with mechano-signaling between cardiomyocytes and the extracellular matrix and inflammation were altered in LV and EN samples. In addition, EN samples had larger differences in pathways related to metabolic dysfunction compared to LV. Our findings provide a translational understanding of signaling pathways altered in the MYH7-R403Q gene variant.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100495"},"PeriodicalIF":2.2,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145467015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-31DOI: 10.1016/j.jmccpl.2025.100494
Fang Xu , Min Wu , Yihan Wang , Haiyan Luo , Xiaobo Gao , Song Lai , Cailing Lu
Prolonged cardiac hypertrophy is a main risk factor for heart failure (HF). During cardiac hypertrophy remodelling, there is an increase in protein synthesis, as well as the trafficking and localization of proteins to their functional sites. Rab GTPases, which are key regulators of vesicular formation, movement, and fusion, play a crucial role in these processes. In this study, we identified Rab10, a small GTPase belonging to the Rab family, as a novel regulator to inhibit cardiac hypertrophy. Cardiomyocyte hypertrophy was induced by Ang II or pressure overload in primary neonatal rat cardiomyocytes (NRCMs) or mouse model. We found that Rab10 expression was downregulated in NRCMs or murine hearts after hypertrophic stress. Rab10 overexpression attenuated cardiomyocyte hypertrophy, whereas its silencing exacerbated the phenotype, demonstrating its essential antihypertrophic role in vitro. To determine the in vivo role of Rab10 in the heart, we generated cardiac-specific Rab10-overexpressing transgenic mice (TG). When subjected to Ang II infusion or pressure overload, Rab10 TG mice displayed an improved contractile function and attenuated hypertrophic remodelling. In contrast, AAV9-mediated cardiac-specific knockdown of Rab10 significantly aggravated pressure overload-induced cardiomyocyte hypertrophy. Mechanically, Rab10 suppressed the phosphorylation of ERK1/2 and AKT, thereby attenuating the development cardiac hypertrophy. Additionally, we demonstrated that Rab10 was post-transcriptionally downregulated by miR-199a. In summary, our findings revealed a novel role for Rab10 in pathogenic cardiac hypertrophy and suggest that Rab10 may be a potential therapeutic target for cardiac hypertrophic.
{"title":"Rab10 plays a protective role in the development of pathological cardiac hypertrophy","authors":"Fang Xu , Min Wu , Yihan Wang , Haiyan Luo , Xiaobo Gao , Song Lai , Cailing Lu","doi":"10.1016/j.jmccpl.2025.100494","DOIUrl":"10.1016/j.jmccpl.2025.100494","url":null,"abstract":"<div><div>Prolonged cardiac hypertrophy is a main risk factor for heart failure (HF). During cardiac hypertrophy remodelling, there is an increase in protein synthesis, as well as the trafficking and localization of proteins to their functional sites. Rab GTPases, which are key regulators of vesicular formation, movement, and fusion, play a crucial role in these processes. In this study, we identified Rab10, a small GTPase belonging to the Rab family, as a novel regulator to inhibit cardiac hypertrophy. Cardiomyocyte hypertrophy was induced by Ang II or pressure overload in primary neonatal rat cardiomyocytes (NRCMs) or mouse model. We found that Rab10 expression was downregulated in NRCMs or murine hearts after hypertrophic stress. Rab10 overexpression attenuated cardiomyocyte hypertrophy, whereas its silencing exacerbated the phenotype, demonstrating its essential antihypertrophic role <em>in vitro</em>. To determine the <em>in vivo</em> role of Rab10 in the heart, we generated cardiac-specific Rab10-overexpressing transgenic mice (TG). When subjected to Ang II infusion or pressure overload, Rab10 TG mice displayed an improved contractile function and attenuated hypertrophic remodelling. In contrast, AAV9-mediated cardiac-specific knockdown of Rab10 significantly aggravated pressure overload-induced cardiomyocyte hypertrophy. Mechanically, Rab10 suppressed the phosphorylation of ERK1/2 and AKT, thereby attenuating the development cardiac hypertrophy. Additionally, we demonstrated that Rab10 was post-transcriptionally downregulated by miR-199a. In summary, our findings revealed a novel role for Rab10 in pathogenic cardiac hypertrophy and suggest that Rab10 may be a potential therapeutic target for cardiac hypertrophic.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100494"},"PeriodicalIF":2.2,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145520323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiovascular complications are the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D), which is recognized as a major independent risk factor for coronary artery disease, stroke, peripheral vascular disease, and heart failure. The interrelationship between metabolic dysfunction and cardiovascular disease is complex and multifactorial, involving hyperglycemia, insulin resistance, inflammation, and oxidative stress. Evidence indicates that endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR) contribute to metabolic dysregulation and vascular dysfunction. However, the specific role of beta cell-derived UPR mediators, particularly C/EBP homologous protein (CHOP), in coordinating this interorgan axis between the endocrine pancreas and the cardiovascular system remains poorly understood.
Methods
To determine the role of beta cell CHOP in mediating the link between T2D and cardiovascular complications, we specifically deleted CHOP in beta cells. Thus, male and female β-cellflox/flox and β-cell-specific CHOP knockout (β-cellCHOP−/−) mice were fed a high-fat diet (HFD) or a control diet for four months. Metabolic, cardiovascular, and inflammatory parameters were assessed, including body weight, exercise capacity as measured by running distance, organ weights (heart, lung, pancreas, and kidney), glucose tolerance test (GTT), vascular endothelial function, cardiac fibrosis, and the expression of ER stress and inflammatory signaling markers.
Results
β-cellflox/flox mice fed HFD for four months develop hallmark features of T2D, including obesity, glucose intolerance, impaired exercise capacity, cardiac fibrosis, vascular endothelial dysfunction, and increased organ weights. In contrast, β-cellCHOP−/− mice are protected from these complications, demonstrating preserved glucose tolerance, endothelial function, reduced cardiac fibrosis, enhanced exercise performance, and blunted activation of ER stress and inflammatory pathways.
Conclusion
This study elucidates CHOP in pancreatic beta cells as a key mechanism linking T2D to cardiovascular complications. Deleting CHOP in beta cells reduces metabolic and cardiovascular issues, underscoring the role of beta cell stress in the connection between T2D and cardiovascular disease. These findings suggest that CHOP may be a potential target for preventing T2D-related cardiovascular complications.
{"title":"Deletion of CHOP in beta cell protects mice from cardiovascular complications in type 2 diabetes: evidence from a pre-clinical mouse model","authors":"Balaji Srinivas , Kiran Alluri , Nour-Eddine Rhaleb , Khalid Matrougui","doi":"10.1016/j.jmccpl.2025.100492","DOIUrl":"10.1016/j.jmccpl.2025.100492","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular complications are the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D), which is recognized as a major independent risk factor for coronary artery disease, stroke, peripheral vascular disease, and heart failure. The interrelationship between metabolic dysfunction and cardiovascular disease is complex and multifactorial, involving hyperglycemia, insulin resistance, inflammation, and oxidative stress. Evidence indicates that endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR) contribute to metabolic dysregulation and vascular dysfunction. However, the specific role of beta cell-derived UPR mediators, particularly C/EBP homologous protein (CHOP), in coordinating this interorgan axis between the endocrine pancreas and the cardiovascular system remains poorly understood.</div></div><div><h3>Methods</h3><div>To determine the role of beta cell CHOP in mediating the link between T2D and cardiovascular complications, we specifically deleted CHOP in beta cells. Thus, male and female β-cell<sup>flox/flox</sup> and β-cell-specific CHOP knockout (β-cell<sup>CHOP−/−</sup>) mice were fed a high-fat diet (HFD) or a control diet for four months. Metabolic, cardiovascular, and inflammatory parameters were assessed, including body weight, exercise capacity as measured by running distance, organ weights (heart, lung, pancreas, and kidney), glucose tolerance test (GTT), vascular endothelial function, cardiac fibrosis, and the expression of ER stress and inflammatory signaling markers.</div></div><div><h3>Results</h3><div>β-cell<sup>flox/flox</sup> mice fed HFD for four months develop hallmark features of T2D, including obesity, glucose intolerance, impaired exercise capacity, cardiac fibrosis, vascular endothelial dysfunction, and increased organ weights. In contrast, β-cell<sup>CHOP−/−</sup> mice are protected from these complications, demonstrating preserved glucose tolerance, endothelial function, reduced cardiac fibrosis, enhanced exercise performance, and blunted activation of ER stress and inflammatory pathways.</div></div><div><h3>Conclusion</h3><div>This study elucidates CHOP in pancreatic beta cells as a key mechanism linking T2D to cardiovascular complications. Deleting CHOP in beta cells reduces metabolic and cardiovascular issues, underscoring the role of beta cell stress in the connection between T2D and cardiovascular disease. These findings suggest that CHOP may be a potential target for preventing T2D-related cardiovascular complications.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100492"},"PeriodicalIF":2.2,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-19DOI: 10.1016/j.jmccpl.2025.100491
Lars Saemann , Lotta Hartrumpf , Adrian-Iustin Georgevici , Sabine Pohl , Anne Großkopf , Kristin Wächter , Yuxing Guo , Andreas Simm , Gábor Szabó
Introduction
Vascular aging is associated with endothelial dysfunction, changes in vascular elasticity or stiffness, and the prevalence of cardiovascular diseases. Aging differs by sex. The effects of age, sex, and vessel region on arterial vasomotor function and gene expression signatures have not been explored yet. Thus, we investigated contraction, relaxation, and endothelial integrity, as well as gene expression, in the proximal and distal segments of the thoracic aorta in 6- and 18-month-old mice.
Materials and methods
Male and female C57BL/6J mice at 6 (n = 11/sex) and 18 (n = 12/sex) months of age were used. Segments of the proximal and distal thoracic aorta were mounted in organ bath chambers. We assessed the maximal receptor-independent contractility using potassium chloride (KCl), endothelial integrity using phenylephrine (PE), endothelial-dependent relaxation using acetylcholine (ACh), and endothelial-independent relaxation using sodium nitroprusside (SNP). Using microarrays, we performed transcriptomics on another 6 six mice of every subgroup.
Results
Endothelial integrity decreases significantly with age in male mice, but only in the proximal segment. The relaxation to ACh decreases with age in both sexes in the proximal and only in female individuals in the descending segment. In females, endothelial-dependent relaxation is higher than in males, in young age, independent of the segment, and in old age, still in the proximal segment. Endothelial-independent relaxation decreases with age only in the distal segment of female subjects. Genes associated with the electron transport chain, crucial for energy production in mitochondria, are decreased by age. The G-protein coupled receptor -G13 alpha subunit- signaling pathway and proteasome degradation, which are crucial for developing and maintaining endothelial integrity, were reduced in the aorta of old mice. Genes involved in endothelial nitric oxide synthesis were especially downregulated in old male mice.
Conclusion
Endothelial integrity and endothelial-dependent relaxation depend on age, sex, and segment of the descending thoracic aorta in mice. Genes associated with endothelial-dependent relaxation, endothelial integrity, and vascular aging change markedly by age, including some sex- and segment-specific differences.
{"title":"Age, sex, and vessel region affect the vasomotor function and gene expression signature of the aorta in mice","authors":"Lars Saemann , Lotta Hartrumpf , Adrian-Iustin Georgevici , Sabine Pohl , Anne Großkopf , Kristin Wächter , Yuxing Guo , Andreas Simm , Gábor Szabó","doi":"10.1016/j.jmccpl.2025.100491","DOIUrl":"10.1016/j.jmccpl.2025.100491","url":null,"abstract":"<div><h3>Introduction</h3><div>Vascular aging is associated with endothelial dysfunction, changes in vascular elasticity or stiffness, and the prevalence of cardiovascular diseases. Aging differs by sex. The effects of age, sex, and vessel region on arterial vasomotor function and gene expression signatures have not been explored yet. Thus, we investigated contraction, relaxation, and endothelial integrity, as well as gene expression, in the proximal and distal segments of the thoracic aorta in 6- and 18-month-old mice.</div></div><div><h3>Materials and methods</h3><div>Male and female C57BL/6J mice at 6 (<em>n</em> = 11/sex) and 18 (<em>n</em> = 12/sex) months of age were used. Segments of the proximal and distal thoracic aorta were mounted in organ bath chambers. We assessed the maximal receptor-independent contractility using potassium chloride (KCl), endothelial integrity using phenylephrine (PE), endothelial-dependent relaxation using acetylcholine (ACh), and endothelial-independent relaxation using sodium nitroprusside (SNP). Using microarrays, we performed transcriptomics on another 6 six mice of every subgroup.</div></div><div><h3>Results</h3><div>Endothelial integrity decreases significantly with age in male mice, but only in the proximal segment. The relaxation to ACh decreases with age in both sexes in the proximal and only in female individuals in the descending segment. In females, endothelial-dependent relaxation is higher than in males, in young age, independent of the segment, and in old age, still in the proximal segment. Endothelial-independent relaxation decreases with age only in the distal segment of female subjects. Genes associated with the electron transport chain, crucial for energy production in mitochondria, are decreased by age. The G-protein coupled receptor -G13 alpha subunit- signaling pathway and proteasome degradation, which are crucial for developing and maintaining endothelial integrity, were reduced in the aorta of old mice. Genes involved in endothelial nitric oxide synthesis were especially downregulated in old male mice.</div></div><div><h3>Conclusion</h3><div>Endothelial integrity and endothelial-dependent relaxation depend on age, sex, and segment of the descending thoracic aorta in mice. Genes associated with endothelial-dependent relaxation, endothelial integrity, and vascular aging change markedly by age, including some sex- and segment-specific differences.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100491"},"PeriodicalIF":2.2,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-17DOI: 10.1016/j.jmccpl.2025.100489
Mahmoud Balata , Abdelrahman M.Attia , Mohamed Ibrahim Gbreel , Mamdouh Elsmaan , Marwa Hassan , Paul Rapeanu , Milka Marinova , Marc Ulrich Becher , Islam Ebeid , Jasmin Ortak , Hüseyin Ince
Introduction
Cardiac amyloidosis (CA) impacts about 20 % of elderly heart failure patients, leading to myocardial dysfunction and life-threatening risks. However, it often remains undetected due to the significant risks associated with invasive biopsies. This highlights the critical need for safer and accurate non-invasive diagnostic techniques.
Aim
To compare the diagnostic value of Cardiac Magnetic Resonance (CMR) imaging and Cardiac Scintigraphy Imaging in the diagnosis of CA.
Methods
A comprehensive literature search across PubMed, Scopus, Web of Science, and Cochrane databases yielded studies that utilized CMR or cardiac scintigraphy for diagnosing CA. QUADAS-2 was employed for quality assessment.
Results
From 7117 records, 35 studies involving 4866 patients were analyzed. Cardiac scintigraphy demonstrated higher sensitivity and specificity across different radiotracers, with 99mTc-HMDP showing the highest specificity (1.00, 95 % CI: 0.93–1.00) and 99mTc-DPD the highest sensitivity (0.93, 95 % CI: 0.89–0.95). CMR imaging showed variable diagnostic accuracy with a sensitivity of 0.83 (95 % CI: 0.81–0.85) and a lower specificity of only 0.53 (95 % CI: 0.50–0.56).
Conclusion
Cardiac scintigraphy, particularly with 99mTc-HMDP, offers superior diagnostic accuracy for CA compared to CMR imaging. Controlled, randomized, prospective studies directly comparing these non-invasive techniques are essential to validate these findings.
{"title":"Cardiac magnetic resonance imaging and cardiac scintigraphy in the diagnosis of cardiac amyloidosis: A meta-analysis of 4866 patients","authors":"Mahmoud Balata , Abdelrahman M.Attia , Mohamed Ibrahim Gbreel , Mamdouh Elsmaan , Marwa Hassan , Paul Rapeanu , Milka Marinova , Marc Ulrich Becher , Islam Ebeid , Jasmin Ortak , Hüseyin Ince","doi":"10.1016/j.jmccpl.2025.100489","DOIUrl":"10.1016/j.jmccpl.2025.100489","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiac amyloidosis (CA) impacts about 20 % of elderly heart failure patients, leading to myocardial dysfunction and life-threatening risks. However, it often remains undetected due to the significant risks associated with invasive biopsies. This highlights the critical need for safer and accurate non-invasive diagnostic techniques.</div></div><div><h3>Aim</h3><div>To compare the diagnostic value of Cardiac Magnetic Resonance (CMR) imaging and Cardiac Scintigraphy Imaging in the diagnosis of CA.</div></div><div><h3>Methods</h3><div>A comprehensive literature search across PubMed, Scopus, Web of Science, and Cochrane databases yielded studies that utilized CMR or cardiac scintigraphy for diagnosing CA. QUADAS-2 was employed for quality assessment.</div></div><div><h3>Results</h3><div>From 7117 records, 35 studies involving 4866 patients were analyzed. Cardiac scintigraphy demonstrated higher sensitivity and specificity across different radiotracers, with 99mTc-HMDP showing the highest specificity (1.00, 95 % CI: 0.93–1.00) and 99mTc-DPD the highest sensitivity (0.93, 95 % CI: 0.89–0.95). CMR imaging showed variable diagnostic accuracy with a sensitivity of 0.83 (95 % CI: 0.81–0.85) and a lower specificity of only 0.53 (95 % CI: 0.50–0.56).</div></div><div><h3>Conclusion</h3><div>Cardiac scintigraphy, particularly with 99mTc-HMDP, offers superior diagnostic accuracy for CA compared to CMR imaging. Controlled, randomized, prospective studies directly comparing these non-invasive techniques are essential to validate these findings.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100489"},"PeriodicalIF":2.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.jmccpl.2025.100490
Niko Schwenzer , Roman Tsukanov , Tobias Kohl , Samrat Basak , Izzatullo Sobitov , Fitzwilliam Seibertz , Rohan Kapoor , Niels Voigt , Jörg Enderlein , Stephan E. Lehnart
The clustering of L-type calcium channels (LTCC) for functional regulation of intracellular calcium signaling remains poorly understood. Here we applied super-resolution imaging to study CaV1.3 channel clusters in human iPSC-derived atrial cardiomyocytes (hiPSC-aCM) to analyze subcellular localization, dimensions, architecture, and dynamics, which were largely unexplored previously. STimulated Emission Depletion (STED) imaging characterized the localization and structure of CaV1.3 channel clusters in living cardiomyocytes. DNA Points Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) achieved true molecular resolution, revealing an irregular channel distribution with substantial spacing. Single Particle Tracking (SPT) showed that channels co-diffuse in confined and stationary membrane nanodomains. The cytosolic C-terminal tail of CaV1.3 by itself was found sufficient for cluster formation. In conclusion, our LTCC clustering studies demonstrate that CaV1.3 channel clusters consist of mobile individual channels inside defined membrane nanodomains, in contrast to previous models of dense channel packing.
{"title":"Nanoscale architecture and dynamics of CaV1.3 channel clusters in cardiac myocytes revealed by single channel nanoscopy","authors":"Niko Schwenzer , Roman Tsukanov , Tobias Kohl , Samrat Basak , Izzatullo Sobitov , Fitzwilliam Seibertz , Rohan Kapoor , Niels Voigt , Jörg Enderlein , Stephan E. Lehnart","doi":"10.1016/j.jmccpl.2025.100490","DOIUrl":"10.1016/j.jmccpl.2025.100490","url":null,"abstract":"<div><div>The clustering of L-type calcium channels (LTCC) for functional regulation of intracellular calcium signaling remains poorly understood. Here we applied super-resolution imaging to study Ca<sub>V</sub>1.3 channel clusters in human iPSC-derived atrial cardiomyocytes (hiPSC-aCM) to analyze subcellular localization, dimensions, architecture, and dynamics, which were largely unexplored previously. STimulated Emission Depletion (STED) imaging characterized the localization and structure of Ca<sub>V</sub>1.3 channel clusters in living cardiomyocytes. DNA Points Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) achieved true molecular resolution, revealing an irregular channel distribution with substantial spacing. Single Particle Tracking (SPT) showed that channels co-diffuse in confined and stationary membrane nanodomains. The cytosolic C-terminal tail of Ca<sub>V</sub>1.3 by itself was found sufficient for cluster formation. In conclusion, our LTCC clustering studies demonstrate that Ca<sub>V</sub>1.3 channel clusters consist of mobile individual channels inside defined membrane nanodomains, in contrast to previous models of dense channel packing.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100490"},"PeriodicalIF":2.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145364043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-05DOI: 10.1016/j.jmccpl.2025.100487
Fatima Daoud , Johan Holmberg , Hanna Winter , Nadja Sachs , Lars Maegdefessel , Sebastian Albinsson
The transcriptional co-activators YAP (YAP1) and TAZ (WWTR1) are central regulators of vascular smooth muscle cell (VSMC) phenotype and vascular homeostasis. This study investigates the consequences of VSMC-specific YAP/TAZ deletion and its relevance to atherosclerosis. Using bulk and single-cell RNA sequencing data, we demonstrate that gene expression changes following two (2-week YT) and eight weeks (8-week YT) of YAP/TAZ deletion recapitulate key features of murine and human atherosclerosis. Transcriptomic comparisons revealed substantial overlap and concordance between YAP/TAZ-deficient VSMCs and different stages of plaque development, with 8-week YT displaying stronger resemblance to atherosclerotic lesions. Shared differentially expressed genes were enriched for inflammatory mediators, extracellular matrix remodeling factors, and chondrogenic markers. Gene ontology and Reactome pathway enrichment analyses highlighted upregulation of immune-related pathways, extracellular matrix remodeling, and chondrogenic differentiation, accompanied by the downregulation of muscle contractile programs. Integration of ChIP-seq data and promoter motif analyses identified 19 conserved YAP–TEAD target genes that were consistently repressed at both 2-week and 8-week YT. Several of these target genes were also downregulated in atherosclerotic plaques, such as genes involved in cytoskeletal integrity (e.g., SRF, NEXN). Notably, loss of YAP/TAZ induced a phenotypic shift in VSMCs toward chondromyocyte-like and fibromyocyte-like states, analogous to those seen in murine and human atherosclerosis. These findings suggest that YAP/TAZ safeguard VSMC identity by directly repressing pro-inflammatory and osteochondrogenic programs, and that their disruption may contribute to atherogenesis. This positions YAP/TAZ–TEAD axis as a key guardian of vascular homeostasis and a potential therapeutic target for limiting plaque progression.
{"title":"YAP/TAZ deletion in vascular smooth muscle cells mirrors atherosclerosis-associated transcriptional programs","authors":"Fatima Daoud , Johan Holmberg , Hanna Winter , Nadja Sachs , Lars Maegdefessel , Sebastian Albinsson","doi":"10.1016/j.jmccpl.2025.100487","DOIUrl":"10.1016/j.jmccpl.2025.100487","url":null,"abstract":"<div><div>The transcriptional co-activators YAP (<em>YAP1</em>) and TAZ (<em>WWTR1</em>) are central regulators of vascular smooth muscle cell (VSMC) phenotype and vascular homeostasis. This study investigates the consequences of VSMC-specific YAP/TAZ deletion and its relevance to atherosclerosis. Using bulk and single-cell RNA sequencing data, we demonstrate that gene expression changes following two (2-week YT) and eight weeks (8-week YT) of YAP/TAZ deletion recapitulate key features of murine and human atherosclerosis. Transcriptomic comparisons revealed substantial overlap and concordance between YAP/TAZ-deficient VSMCs and different stages of plaque development, with 8-week YT displaying stronger resemblance to atherosclerotic lesions. Shared differentially expressed genes were enriched for inflammatory mediators, extracellular matrix remodeling factors, and chondrogenic markers. Gene ontology and Reactome pathway enrichment analyses highlighted upregulation of immune-related pathways, extracellular matrix remodeling, and chondrogenic differentiation, accompanied by the downregulation of muscle contractile programs. Integration of ChIP-seq data and promoter motif analyses identified 19 conserved YAP–TEAD target genes that were consistently repressed at both 2-week and 8-week YT. Several of these target genes were also downregulated in atherosclerotic plaques, such as genes involved in cytoskeletal integrity (e.g., <em>SRF, NEXN</em>). Notably, loss of YAP/TAZ induced a phenotypic shift in VSMCs toward chondromyocyte-like and fibromyocyte-like states, analogous to those seen in murine and human atherosclerosis. These findings suggest that YAP/TAZ safeguard VSMC identity by directly repressing pro-inflammatory and osteochondrogenic programs, and that their disruption may contribute to atherogenesis. This positions YAP/TAZ–TEAD axis as a key guardian of vascular homeostasis and a potential therapeutic target for limiting plaque progression.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100487"},"PeriodicalIF":2.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-03DOI: 10.1016/j.jmccpl.2025.100486
Nicole S. York , Joel E. Rivera , Mohammadreza Rahmani Manesh , K’sana Wood Lynes-Ford , Rory Smith , Leigh E. Wicki-Stordeur , Laura T. Arbour , Leigh Anne Swayne
Cell culture models enable advancement in our understanding of heart development and heart disease. The H9c2 rat ventricular cardiomyoblast cell line can be differentiated with retinoic acid and low serum, leading to morphological, molecular, and functional changes that partially resemble aspects of cardiomyoblast-to-cardiomyocyte differentiation. However, morphological, functional, and biochemical changes are rarely investigated in parallel, thereby limiting fulsome understanding of how these processes are interlinked, and to what extent these model cardiomyoblasts can be differentiated. To provide a parallel analysis as a resource for future studies, we therefore characterized H9c2 cell morphology, Ca2+ handling, and gene expression after five days (5 days-in-vitro, DIV5), and fourteen days (DIV14) of exposure to differentiation stimuli, consisting of retinoic acid and low serum. We observed statistically significant morphological changes during differentiation. We saw changes consistent with those already described in the context of cardiomyoblast differentiation. However, some of these were previously limited to qualitative observations, for example increased cell length. Notably, several of our morphological observations are completely novel, such as increases in eccentricity, perimeter length (aka cell boundary length), and in the density of actin clusters, were investigated de novo. Differentiation also resulted in the onset of spontaneous Ca2+ transients – this is the first instance, to our knowledge, that this has been characterized in the absence of pharmacological stimulation. The mean frequency and synchronicity of Ca2+ transients in differentiated H9c2 cells were much lower than those observed in primary cardiomyocytes, underscoring their relatively immature differentiation state from a functional perspective. Additionally, key cardiomyocyte cytoskeletal proteins and ion channel transcript and protein expression levels changed significantly with differentiation, including at early timepoints (DIV5 h and DIV3) which had not yet been investigated by others, in alignment with changes normally observed in cardiomyocyte development. Overall, our findings position differentiated H9c2 cells as a relatively high-throughput model for studying cardiomyoblast differentiation, while also clarifying their limitations in recapitulating fully mature cardiomyocyte phenotypes, and highlight reliable markers (e.g., Cacna1c, Myom2, cTnT, VCL, and Gja5) for experimental readouts.
{"title":"Quantification of morphological, functional, and biochemical features of H9c2 rat cardiomyoblast retinoic acid differentiation","authors":"Nicole S. York , Joel E. Rivera , Mohammadreza Rahmani Manesh , K’sana Wood Lynes-Ford , Rory Smith , Leigh E. Wicki-Stordeur , Laura T. Arbour , Leigh Anne Swayne","doi":"10.1016/j.jmccpl.2025.100486","DOIUrl":"10.1016/j.jmccpl.2025.100486","url":null,"abstract":"<div><div>Cell culture models enable advancement in our understanding of heart development and heart disease. The H9c2 rat ventricular cardiomyoblast cell line can be differentiated with retinoic acid and low serum, leading to morphological, molecular, and functional changes that partially resemble aspects of cardiomyoblast-to-cardiomyocyte differentiation. However, morphological, functional, and biochemical changes are rarely investigated in parallel, thereby limiting fulsome understanding of how these processes are interlinked, and to what extent these model cardiomyoblasts can be differentiated. To provide a parallel analysis as a resource for future studies, we therefore characterized H9c2 cell morphology, Ca<sup>2+</sup> handling, and gene expression after five days (5 days<em>-in-vitro</em>, DIV5), and fourteen days (DIV14) of exposure to differentiation stimuli, consisting of retinoic acid and low serum. We observed statistically significant morphological changes during differentiation. We saw changes consistent with those already described in the context of cardiomyoblast differentiation. However, some of these were previously limited to qualitative observations, for example increased cell length. Notably, several of our morphological observations are completely novel, such as increases in eccentricity, perimeter length (aka cell boundary length), and in the density of actin clusters, were investigated de novo. Differentiation also resulted in the onset of spontaneous Ca<sup>2+</sup> transients – this is the first instance, to our knowledge, that this has been characterized in the absence of pharmacological stimulation. The mean frequency and synchronicity of Ca<sup>2+</sup> transients in differentiated H9c2 cells were much lower than those observed in primary cardiomyocytes, underscoring their relatively immature differentiation state from a functional perspective. Additionally, key cardiomyocyte cytoskeletal proteins and ion channel transcript and protein expression levels changed significantly with differentiation, including at early timepoints (DIV5 h and DIV3) which had not yet been investigated by others, in alignment with changes normally observed in cardiomyocyte development. Overall, our findings position differentiated H9c2 cells as a relatively high-throughput model for studying cardiomyoblast differentiation, while also clarifying their limitations in recapitulating fully mature cardiomyocyte phenotypes, and highlight reliable markers (e.g., <em>Cacna1c, Myom2</em>, cTnT, VCL, and <em>Gja5</em>) for experimental readouts.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100486"},"PeriodicalIF":2.2,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-02DOI: 10.1016/j.jmccpl.2025.100488
Omar Kayyem , Ruonan Gu , Ying Xia , Jerry Wang , Aizhu Lu , Hongwei Wang , Darryl R. Davis , Peter Liu , Wenbin Liang
Background
Both Nav1.5 and Cx43 are critical for the fast electrical impulse conduction in the myocardium and their reductions create the arrhythmogenic substrate. Wnt/β-catenin signaling is activated in arrhythmogenic myocardium, and although this signaling is known to downregulate cardiac Nav1.5, its regulation of Cx43 is unclear as conflicting results have been reported. The present study investigated how Wnt/β-catenin signaling regulates Cx43 in rat and human cardiomyocytes and if it is dependent on the sex of the cells or the metabolic substrates.
Methods
Male and female neonatal rat ventricular myocytes (NRVMs) were treated with CHIR-99021 (CHIR) or Wnt3a protein, two different activators of the Wnt/β-catenin signaling, either in a medium rich in glucose (a preferred metabolic substrate in heart failure) or in a medium rich in lipid (∼150 μM fatty acid, a preferred substrate in healthy hearts). Both healthy and Brugada Syndrome human iPSC-derived cardiomyocytes (iPSC-CMs) were used to confirm observations in NRVMs.
Results
When maintained in a glucose-rich medium, Gja1 mRNA (encoding Cx43) was reduced by a low concentration of CHIR (1 μM) in female NRVMs but only at a high concentration of CHIR (10 μM) in male NRVMs. However, reductions in Cx43 protein were observed at 1 μM CHIR in both male and female NRVMs, suggesting the involvement of both transcriptional and post-transcriptional mechanisms. When maintained in a lipid-rich medium, neither Gja1 mRNA nor Cx43 protein was altered by CHIR at 1 or 3 μM. In contrast, CHIR-induced reductions in Scn5a mRNA and Nav1.5 protein were observed in both glucose-rich and lipid-rich media, with no significant sex-specific differences detected. Consistent with studies using CHIR, which is a Wnt receptor-independent activator, Wnt3a protein also reduced both Gja1 mRNA and Cx43 protein in NRVMs in the glucose-rich medium but not in the lipid-rich medium. In human iPSC-CMs from two healthy volunteers and one Brugada Syndrome patient, Wnt/β-catenin signaling activation reduced GJA1 mRNA and Cx43 protein in a standard, glucose-containing medium.
Conclusions
These data demonstrate that metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes, with reductions in Cx43 mRNA and protein only observed when glucose is the primary metabolic substrate, which occurs in arrhythmogenic conditions such as cardiac hypertrophy and heart failure.
{"title":"Wnt/β-catenin signaling regulates cardiac Cx43 in a metabolic substrate-dependent manner","authors":"Omar Kayyem , Ruonan Gu , Ying Xia , Jerry Wang , Aizhu Lu , Hongwei Wang , Darryl R. Davis , Peter Liu , Wenbin Liang","doi":"10.1016/j.jmccpl.2025.100488","DOIUrl":"10.1016/j.jmccpl.2025.100488","url":null,"abstract":"<div><h3>Background</h3><div>Both Na<sub>v</sub>1.5 and Cx43 are critical for the fast electrical impulse conduction in the myocardium and their reductions create the arrhythmogenic substrate. Wnt/β-catenin signaling is activated in arrhythmogenic myocardium, and although this signaling is known to downregulate cardiac Na<sub>v</sub>1.5, its regulation of Cx43 is unclear as conflicting results have been reported. The present study investigated how Wnt/β-catenin signaling regulates Cx43 in rat and human cardiomyocytes and if it is dependent on the sex of the cells or the metabolic substrates.</div></div><div><h3>Methods</h3><div>Male and female neonatal rat ventricular myocytes (NRVMs) were treated with CHIR-99021 (CHIR) or Wnt3a protein, two different activators of the Wnt/β-catenin signaling, either in a medium rich in glucose (a preferred metabolic substrate in heart failure) or in a medium rich in lipid (∼150 μM fatty acid, a preferred substrate in healthy hearts). Both healthy and Brugada Syndrome human iPSC-derived cardiomyocytes (iPSC-CMs) were used to confirm observations in NRVMs.</div></div><div><h3>Results</h3><div>When maintained in a glucose-rich medium, <em>Gja1</em> mRNA (encoding Cx43) was reduced by a low concentration of CHIR (1 μM) in female NRVMs but only at a high concentration of CHIR (10 μM) in male NRVMs. However, reductions in Cx43 protein were observed at 1 μM CHIR in both male and female NRVMs, suggesting the involvement of both transcriptional and post-transcriptional mechanisms. When maintained in a lipid-rich medium, neither <em>Gja1</em> mRNA nor Cx43 protein was altered by CHIR at 1 or 3 μM. In contrast, CHIR-induced reductions in <em>Scn5a</em> mRNA and Na<sub>v</sub>1.5 protein were observed in both glucose-rich and lipid-rich media, with no significant sex-specific differences detected. Consistent with studies using CHIR, which is a Wnt receptor-independent activator, Wnt3a protein also reduced both <em>Gja1</em> mRNA and Cx43 protein in NRVMs in the glucose-rich medium but not in the lipid-rich medium. In human iPSC-CMs from two healthy volunteers and one Brugada Syndrome patient, Wnt/β-catenin signaling activation reduced <em>GJA1</em> mRNA and Cx43 protein in a standard, glucose-containing medium.</div></div><div><h3>Conclusions</h3><div>These data demonstrate that metabolic substrates regulate the effects of Wnt/β-catenin signaling in cardiomyocytes, with reductions in Cx43 mRNA and protein only observed when glucose is the primary metabolic substrate, which occurs in arrhythmogenic conditions such as cardiac hypertrophy and heart failure.</div></div>","PeriodicalId":73835,"journal":{"name":"Journal of molecular and cellular cardiology plus","volume":"14 ","pages":"Article 100488"},"PeriodicalIF":2.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145269404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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