Estrogen (E2) and estrogen receptors (ERs) play vital roles in conferring cardioprotection by modulating several immunological homeostatic responses in cardiovascular tissues. Over the recent decades, the role of inflammatory responses as a tangential component impacting cardiac function and disease are being appreciated and investigated to elucidate the underlying pathomechanisms, identify and develop therapeutic strategies; thus, the emergence of the multi-disciplinary field—cardioimmunology. Here, after summarizing expressions and functionalities of ERs in cellular constituents of the cardiovascular system, we discuss synergistic estrogenic signaling mechanisms preserving cardiovascular function and immune homeostasis. Next, we review studies implicating E2 and ERs in inflammation-driven cardiovascular disease initiation and progression and highlight therapeutic strategies and clinical implications to foster further research into promoting cardiovascular health.
{"title":"Estrogen and Estrogen Receptors in Cardioimmunology: Implications in Physiology, Pathophysiology, and Therapeutic Strategies","authors":"Hongjian Hou, Gabriel K. Adzika","doi":"10.1111/apha.70124","DOIUrl":"10.1111/apha.70124","url":null,"abstract":"<div>\u0000 \u0000 <p>Estrogen (E2) and estrogen receptors (ERs) play vital roles in conferring cardioprotection by modulating several immunological homeostatic responses in cardiovascular tissues. Over the recent decades, the role of inflammatory responses as a tangential component impacting cardiac function and disease are being appreciated and investigated to elucidate the underlying pathomechanisms, identify and develop therapeutic strategies; thus, the emergence of the multi-disciplinary field—cardioimmunology. Here, after summarizing expressions and functionalities of ERs in cellular constituents of the cardiovascular system, we discuss synergistic estrogenic signaling mechanisms preserving cardiovascular function and immune homeostasis. Next, we review studies implicating E2 and ERs in inflammation-driven cardiovascular disease initiation and progression and highlight therapeutic strategies and clinical implications to foster further research into promoting cardiovascular health.</p>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399137","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}
Shayla Sharmine, Thomas Aga Legøy, Lucas Unger, Joao A. Paulo, Luiza Ghila, Simona Chera
Aim
HNF1A-MODY, the most prevalent form of monogenic diabetes, displays incomplete penetrance, indicating the involvement of other environmental and genetic factors in the disease etiology. Currently, it is largely unknown what the influence of environmental factors, such as toxins or diet, is on HNF1A-MODY onset and progression. Here we address this issue by exploring the impact of diet on islet and insulin-secreting beta-cells in the context of HNF1A mutation.
Methods
Transgenic mice allowing the specific Hnf1a mutation in insulin-secreting beta-cells were exposed to four distinct dietary regimens including combinations of high-fat diet and caloric restriction. In vitro stem cell islets bearing the HNF1AP291fsinsC heterozygous mutation and their isogenic controls were used for validation in humans. The readouts included physiological tests, immunofluorescence, proteomics, bulk, and single-cell transcriptomics.
Results
Hnf1a-deficient beta-cells exhibited high sensitivity to dietary cues. Exposure to a high-fat diet exacerbated the glucose regulation defects, while caloric restriction significantly improved blood glucose levels in vivo, without perturbing islet architecture. The high-throughput methods identified changes in the Hnf1a-deficient beta-cells proteome landscape, involving conserved critical regulators of metabolic and growth processes, such as the Carbohydrate Response Element Binding Protein (Chrebp/Mlxipl) and ATP citrate lyase (Acly) among others.
Conclusions
This study hallmarks the important impact of diet on Hnf1a-deficient beta-cells, stemming new therapeutic perspectives, such as future diet management approaches.
{"title":"Caloric Restriction Substantially Improves Glucose Regulation in Mice With Hnf1a-Deficient Beta-Cells","authors":"Shayla Sharmine, Thomas Aga Legøy, Lucas Unger, Joao A. Paulo, Luiza Ghila, Simona Chera","doi":"10.1111/apha.70121","DOIUrl":"10.1111/apha.70121","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>HNF1A-MODY, the most prevalent form of monogenic diabetes, displays incomplete penetrance, indicating the involvement of other environmental and genetic factors in the disease etiology. Currently, it is largely unknown what the influence of environmental factors, such as toxins or diet, is on HNF1A-MODY onset and progression. Here we address this issue by exploring the impact of diet on islet and insulin-secreting beta-cells in the context of HNF1A mutation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transgenic mice allowing the specific Hnf1a mutation in insulin-secreting beta-cells were exposed to four distinct dietary regimens including combinations of high-fat diet and caloric restriction. In vitro stem cell islets bearing the HNF1A<sup>P291fsinsC</sup> heterozygous mutation and their isogenic controls were used for validation in humans. The readouts included physiological tests, immunofluorescence, proteomics, bulk, and single-cell transcriptomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Hnf1a-deficient beta-cells exhibited high sensitivity to dietary cues. Exposure to a high-fat diet exacerbated the glucose regulation defects, while caloric restriction significantly improved blood glucose levels in vivo, without perturbing islet architecture. The high-throughput methods identified changes in the Hnf1a-deficient beta-cells proteome landscape, involving conserved critical regulators of metabolic and growth processes, such as the Carbohydrate Response Element Binding Protein (Chrebp/Mlxipl) and ATP citrate lyase (Acly) among others.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study hallmarks the important impact of diet on Hnf1a-deficient beta-cells, stemming new therapeutic perspectives, such as future diet management approaches.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399151","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}
Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patients, may influence disease progression. Desmin, a muscle-specific intermediate filament protein, is increased in the skeletal muscle of mdx mice, a murine model of DMD with a mild phenotype. Here, we inquired whether desmin acts as a modifier in DMD-associated cardiomyopathy.
Methods
Soluble and insoluble desmin levels were quantified in the hearts of two mdx mouse models (B10.mdx and D2.mdx), and GRMD dystrophic dogs. The expression of desmin-regulatory proteins was also assessed in mdx mice. To assess the impact of desmin levels on the phenotype, we generated mdx mice either desmin-deficient (mdx-Des−/−) or with reduced levels of desmin by introducing a heterozygous desmin knock-out allele (mdx-Des+/−). Phenotypic analyses included cardiac function assessment and histological evaluation.
Results
In mdx mice, desmin was elevated in its insoluble, phosphorylated, and presumably filamentous form, while GRMD dogs with a severe DMD-like phenotype showed no such increase. Desmin deficiency in mdx mice led to severely aggravated dystrophic features, including cardiac dysfunction and increased fibrosis. Moreover, partial desmin reduction in mdx-Des+/− mice led to the abrogation of insoluble desmin increase and worsened the mild mdx dystrophic phenotype.
Conclusion
Increased filamentous desmin appears to be protective in mdx mouse hearts and may modulate the severity of DMD cardiomyopathy. These findings support a modifier role for desmin and highlight this protein as a potential therapeutic target for DMD.
目的：杜氏肌营养不良症（DMD）是一种罕见的x连锁遗传疾病，由于肌营养不良蛋白的缺失而影响骨骼肌和心肌。修饰蛋白，其表达在DMD患者中改变，可能影响疾病进展。Desmin是一种肌肉特异性的中间纤维蛋白，在mdx小鼠骨骼肌中增加，mdx小鼠是一种轻度表型的DMD小鼠模型。在这里，我们探讨了desmin是否作为dmd相关心肌病的调节剂。方法：定量测定两种mdx小鼠模型(B10；mdx和D2。mdx)和GRMD营养不良犬。mdx小鼠中desmin调节蛋白的表达也被评估。为了评估desmin水平对表型的影响，我们通过引入杂合desmin敲除等位基因（mdx- des +/-），产生了desmin缺乏（mdx- des -/-）或desmin水平降低的mdx小鼠。表型分析包括心功能评估和组织学评估。结果：在mdx小鼠中，desmin以其不溶性，磷酸化和可能的丝状形式升高，而具有严重dmd样表型的GRMD犬则没有这种增加。mdx小鼠的Desmin缺乏导致严重加重的营养不良特征，包括心功能障碍和纤维化增加。此外，mdx- des +/-小鼠的部分desmin减少导致不溶性desmin增加的消除，加重了轻度mdx营养不良表型。结论：mdx小鼠心肌丝状蛋白增加具有保护作用，并可能调节DMD心肌病的严重程度。这些发现支持desmin的修饰作用，并强调该蛋白是DMD的潜在治疗靶点。
{"title":"Exploring Desmin as a Potential Modifier in Duchenne Muscular Dystrophy–Associated Cardiomyopathy","authors":"Brice-Emmanuel Guennec, Yeranuhi Hovhannisyan, Gaëlle Revet, Sila Polat, Medhi Hassani, Nathalie Mougenot, Inès Barthelemy, Stephane Blot, Caroline Cieniewski-Bernard, Arnaud Ferry, Ekaterini Kordeli, Zhenlin Li, Onnik Agbulut","doi":"10.1111/apha.70117","DOIUrl":"10.1111/apha.70117","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Duchenne muscular dystrophy (DMD), a rare X-linked genetic disorder, is affecting skeletal and cardiac muscles due to the loss of the dystrophin protein. Modifier proteins, whose expression is altered in DMD patients, may influence disease progression. Desmin, a muscle-specific intermediate filament protein, is increased in the skeletal muscle of mdx mice, a murine model of DMD with a mild phenotype. Here, we inquired whether desmin acts as a modifier in DMD-associated cardiomyopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Soluble and insoluble desmin levels were quantified in the hearts of two mdx mouse models (B10.mdx and D2.mdx), and GRMD dystrophic dogs. The expression of desmin-regulatory proteins was also assessed in mdx mice. To assess the impact of desmin levels on the phenotype, we generated mdx mice either desmin-deficient (mdx-Des<sup>−/−</sup>) or with reduced levels of desmin by introducing a heterozygous desmin knock-out allele (mdx-Des<sup>+/−</sup>). Phenotypic analyses included cardiac function assessment and histological evaluation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In mdx mice, desmin was elevated in its insoluble, phosphorylated, and presumably filamentous form, while GRMD dogs with a severe DMD-like phenotype showed no such increase. Desmin deficiency in mdx mice led to severely aggravated dystrophic features, including cardiac dysfunction and increased fibrosis. Moreover, partial desmin reduction in mdx-Des<sup>+/−</sup> mice led to the abrogation of insoluble desmin increase and worsened the mild mdx dystrophic phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Increased filamentous desmin appears to be protective in mdx mouse hearts and may modulate the severity of DMD cardiomyopathy. These findings support a modifier role for desmin and highlight this protein as a potential therapeutic target for DMD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70117","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benudhara Pati, Martin Jastroch, Naresh Chandra Bal
Background
Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is complex and influenced by lifestyle and (micro)environmental factors, genetic constituents have been considered major predisposing factors. Recent literature shows significant individual variations in both the progression of T2D and the efficacy of antidiabetic drugs. These individual variations are expected to emanate from the inherent genetic make-up and potential epigenetic modifications by environmental factors.
Hypothesis
It has been proposed that altered metabolism (including cellular bioenergetic mechanisms) provides protection from T2D. Moreover, several researchers have proposed that proteins regulating cellular bioenergetics, for example, involved in adaptive thermogenesis, represent good targets to counter T2D. Therefore, we thoroughly searched the literature on genetic variability associated with T2D in this review.
Results
We could only find genes involved in (1) insulin secretion (INS, PDX1, ABCC8, KCNJ11, KCNQ1, CDKAL1, IGFBP2) and (2) cellular bioenergetics in insulin-responsive tissues (INSR, IRS, AKT, SLC2A4, TBC1D4, PPP1R3A, LEP, LEPR, ADIPOQ, TCF7L2, PPAR-γ, SLC30A8). Specific attention is given to diverse ethnic populations, in particular Indian subgroups where these genetic factors may display clearer association to T2D.
Conclusion
By emphasizing genetic predispositions, this review highlights the lack of studies on the genetic association of cellular bioenergetics proteins in T2D pathogenesis. It also underscores the potential for early detection, personalized management, and the development of targeted therapies for individuals with T2D across different genetic profiles.
{"title":"Is Predisposition to T2D Impacted by Polymorphisms in Genes Involved in Insulin Signaling and Cellular Bioenergetics?","authors":"Benudhara Pati, Martin Jastroch, Naresh Chandra Bal","doi":"10.1111/apha.70122","DOIUrl":"10.1111/apha.70122","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Type 2 diabetes (T2D) represents a growing global health challenge, with its prevalence and associated metabolic complications rising sharply over the past two decades. Although the pathogenesis of T2D is complex and influenced by lifestyle and (micro)environmental factors, genetic constituents have been considered major predisposing factors. Recent literature shows significant individual variations in both the progression of T2D and the efficacy of antidiabetic drugs. These individual variations are expected to emanate from the inherent genetic make-up and potential epigenetic modifications by environmental factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Hypothesis</h3>\u0000 \u0000 <p>It has been proposed that altered metabolism (including cellular bioenergetic mechanisms) provides protection from T2D. Moreover, several researchers have proposed that proteins regulating cellular bioenergetics, for example, involved in adaptive thermogenesis, represent good targets to counter T2D. Therefore, we thoroughly searched the literature on genetic variability associated with T2D in this review.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We could only find genes involved in (1) insulin secretion (<i>INS</i>, <i>PDX1</i>, <i>ABCC8</i>, <i>KCNJ11</i>, <i>KCNQ1</i>, <i>CDKAL1</i>, <i>IGFBP2</i>) and (2) cellular bioenergetics in insulin-responsive tissues (<i>INSR</i>, <i>IRS</i>, <i>AKT</i>, <i>SLC2A4</i>, <i>TBC1D4</i>, <i>PPP1R3A</i>, <i>LEP</i>, <i>LEPR</i>, <i>ADIPOQ</i>, <i>TCF7L2</i>, <i>PPAR-γ</i>, <i>SLC30A8</i>). Specific attention is given to diverse ethnic populations, in particular Indian subgroups where these genetic factors may display clearer association to T2D.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>By emphasizing genetic predispositions, this review highlights the lack of studies on the genetic association of cellular bioenergetics proteins in T2D pathogenesis. It also underscores the potential for early detection, personalized management, and the development of targeted therapies for individuals with T2D across different genetic profiles.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 12","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399207","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}
Many physiological parameters, such as heart rate and blood pressure, display pronounced daily rhythms, with significant differences between day and night levels. The ability to anticipate the 24 h cycle of ambient light confers an adaptive advantage, allowing organisms to prepare for periods of activity and rest. Considering chronophysiology is essential when designing, conducting, and interpreting laboratory experiments because of the often considerable amplitude of the rhythms. This review introduces a straightforward mathematical tool to detect 24 h rhythms in physiological datasets. Next, the review examines 24-h diurnal rhythms in heart rate, QT interval, and blood pressure, based on telemetry recordings from conscious, freely moving mice. These examples illustrate how long-term, continuous monitoring of physiological parameters enables precise characterization of daily cycles when present. Furthermore, the large datasets obtained through methods such as telemetry make it possible to determine whether the observed rhythms are dependent on heart rate. Circadian and diurnal rhythms play an essential role in cardiovascular physiology, influencing key parameters such as heart rate and blood pressure. Considering chronophysiology is therefore essential when designing, conducting, and interpreting physiological studies.
{"title":"Twenty-Four Hour Rhythms in Cardiovascular Physiology","authors":"Morten B. Thomsen","doi":"10.1111/apha.70116","DOIUrl":"10.1111/apha.70116","url":null,"abstract":"<p>Many physiological parameters, such as heart rate and blood pressure, display pronounced daily rhythms, with significant differences between day and night levels. The ability to anticipate the 24 h cycle of ambient light confers an adaptive advantage, allowing organisms to prepare for periods of activity and rest. Considering chronophysiology is essential when designing, conducting, and interpreting laboratory experiments because of the often considerable amplitude of the rhythms. This review introduces a straightforward mathematical tool to detect 24 h rhythms in physiological datasets. Next, the review examines 24-h diurnal rhythms in heart rate, QT interval, and blood pressure, based on telemetry recordings from conscious, freely moving mice. These examples illustrate how long-term, continuous monitoring of physiological parameters enables precise characterization of daily cycles when present. Furthermore, the large datasets obtained through methods such as telemetry make it possible to determine whether the observed rhythms are dependent on heart rate. Circadian and diurnal rhythms play an essential role in cardiovascular physiology, influencing key parameters such as heart rate and blood pressure. Considering chronophysiology is therefore essential when designing, conducting, and interpreting physiological studies.</p>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nikole J. Byrne, Christoph Koentges, Katharina Pfeil, Julia C. Lueg, Sayan Bakshi, Aleksandre Tarkhnishvili, Ivan Vosko, Johannes Gollmer, Laura C. Birkle, Thomas Rathner, Stephan Birkle, Sibai Tang, Clara Rau, Michael M. Hoffmann, Katja E. Odening, Stephen Barnes, Landon Shay Wilson, Senka Ljubojevic-Holzer, Markus Wallner, Dirk von Lewinski, Peter Rainer, Simon Sedej, Harald Sourij, Christoph Bode, Adam R. Wende, Andreas Zirlik, Heiko Bugger
Aim
Sirtuin 5 (SIRT5), a mitochondrial NAD+-dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the development of heart failure (HF).
Methods
Mice with cardiomyocyte-specific deletion (cSirt5−/−) or overexpression (cSirt5-Tg) of SIRT5 were generated and subjected to chronic pressure overload by transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography, isolated heart perfusions, and histology. MS-based metabolomics and bulk RNA sequencing were used to explore metabolic and molecular signatures.
Results
cSirt5-Tg mice had similar cardiac structure and function compared to control mice, whereas cSirt5−/− mice displayed exacerbated cardiac dilation and dysfunction following TAC, measured both in vivo by echocardiography and ex vivo in isolated heart perfusions. Metabolomics revealed accumulation of inosine and hypoxanthine, and depletion of adenosine, adenine, AMP, and ADP in cSirt5−/− hearts and following TAC, indicating dysregulation of purine metabolism. RNA-sequencing uncovered upregulation of purine-nucleoside phosphorylase and 5′ nucleotidase, and downregulation of adenosine kinase (ADK) in cSirt5−/− hearts following TAC, indicating dysregulation at the interface of adenosine nucleotide salvage and purine degradation in the absence of SIRT5. Analyses of left ventricular tissue of patients with HF revealed reduced SIRT5 expression correlating with reduced ADK expression.
Conclusion
Loss of SIRT5 in cardiomyocytes aggravates cardiac remodeling and dysfunction in response to chronic pressure overload, involving ATP precursor depletion due to transcriptional dysregulation of cardiac purine metabolism.
{"title":"Cardiomyocyte-Specific Deletion of Sirtuin 5 Accelerates the Development of Heart Failure Upon Dysregulating Purine Metabolism","authors":"Nikole J. Byrne, Christoph Koentges, Katharina Pfeil, Julia C. Lueg, Sayan Bakshi, Aleksandre Tarkhnishvili, Ivan Vosko, Johannes Gollmer, Laura C. Birkle, Thomas Rathner, Stephan Birkle, Sibai Tang, Clara Rau, Michael M. Hoffmann, Katja E. Odening, Stephen Barnes, Landon Shay Wilson, Senka Ljubojevic-Holzer, Markus Wallner, Dirk von Lewinski, Peter Rainer, Simon Sedej, Harald Sourij, Christoph Bode, Adam R. Wende, Andreas Zirlik, Heiko Bugger","doi":"10.1111/apha.70120","DOIUrl":"10.1111/apha.70120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Sirtuin 5 (SIRT5), a mitochondrial NAD<sup>+</sup>-dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the development of heart failure (HF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice with cardiomyocyte-specific deletion (<i>cSirt5</i><sup>−/−</sup>) or overexpression (c<i>Sirt5</i>-Tg) of SIRT5 were generated and subjected to chronic pressure overload by transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography, isolated heart perfusions, and histology. MS-based metabolomics and bulk RNA sequencing were used to explore metabolic and molecular signatures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>c<i>Sirt5</i>-Tg mice had similar cardiac structure and function compared to control mice, whereas c<i>Sirt5</i><sup>−/−</sup> mice displayed exacerbated cardiac dilation and dysfunction following TAC, measured both in vivo by echocardiography and ex vivo in isolated heart perfusions. Metabolomics revealed accumulation of inosine and hypoxanthine, and depletion of adenosine, adenine, AMP, and ADP in c<i>Sirt5</i><sup>−/−</sup> hearts and following TAC, indicating dysregulation of purine metabolism. RNA-sequencing uncovered upregulation of purine-nucleoside phosphorylase and 5′ nucleotidase, and downregulation of adenosine kinase (ADK) in c<i>Sirt5</i><sup>−/−</sup> hearts following TAC, indicating dysregulation at the interface of adenosine nucleotide salvage and purine degradation in the absence of SIRT5. Analyses of left ventricular tissue of patients with HF revealed reduced SIRT5 expression correlating with reduced ADK expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Loss of SIRT5 in cardiomyocytes aggravates cardiac remodeling and dysfunction in response to chronic pressure overload, involving ATP precursor depletion due to transcriptional dysregulation of cardiac purine metabolism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eva Nekvindova, Jaroslav Hrdlicka, Almos Boros, Michaela Slegrova, Alena Kvasilova, Vojtech Skop, Jan Halberstat, Kristyna Holzerova, Jan Neckar, David Sedmera, Veronika Olejnickova
Aim
Left ventricular pressure overload (LVPO) in adults is associated with adverse electrical remodeling, characterized by reduced conduction velocity (CV). However, the progression of LVPO differs when imposed during the proliferative phase of cardiac development. It remains unknown how increased cardiomyocyte proliferation affects LVPO electrical remodeling.
Methods
CV maturation from rat postnatal day (PD) 1 to PD90 and analyzed underlying connexin 43 (Cx43) profile. Pressure overload was induced by abdominal aortic constriction (AAC) in rats during the proliferative phase of cardiac growth (PD2). Animals subjected to AAC during the non-proliferative heart growth (AAC-PD6) and Sham-operated rats served as controls. Electrical remodeling was assessed at PD21 using ECG, optical mapping, western blots, immunofluorescence, and lipidomic analysis, complemented by functional analyses through echocardiography.
Results
Pressure overload led to a 2.5-fold increase in heart weight compared to Sham in both AAC groups. A significant increase in relative left ventricular wall thickening was observed in AAC-PD2 rats only. Optical mapping and ECG showed preserved conduction properties in AAC-PD2 animals, whereas the AAC-PD6 group displayed prolonged QRS and significantly reduced longitudinal CV. While total and phosphorylated Cx43 levels were comparable between the AAC groups, AAC-PD2 animals demonstrated higher intercalated disc localization. Furthermore, lipidomic profiling revealed maintained long-chain acylcarnitine (LCAC) levels in AAC-PD2, whereas AAC-PD6 tended toward LCAC accumulation.
Conclusion
This study provides new insights into the remodeling upon pressure overload during cardiac proliferative growth, demonstrating attenuated electrical alteration by preserved CV and highlighting the role of Cx43 localization and preserved levels of LCACs.
{"title":"Electrical Remodeling of Pressure Overloaded Rat Heart Is Attenuated if Imposed During Proliferative Cardiac Growth","authors":"Eva Nekvindova, Jaroslav Hrdlicka, Almos Boros, Michaela Slegrova, Alena Kvasilova, Vojtech Skop, Jan Halberstat, Kristyna Holzerova, Jan Neckar, David Sedmera, Veronika Olejnickova","doi":"10.1111/apha.70118","DOIUrl":"10.1111/apha.70118","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Left ventricular pressure overload (LVPO) in adults is associated with adverse electrical remodeling, characterized by reduced conduction velocity (CV). However, the progression of LVPO differs when imposed during the proliferative phase of cardiac development. It remains unknown how increased cardiomyocyte proliferation affects LVPO electrical remodeling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>CV maturation from rat postnatal day (PD) 1 to PD90 and analyzed underlying connexin 43 (Cx43) profile. Pressure overload was induced by abdominal aortic constriction (AAC) in rats during the proliferative phase of cardiac growth (PD2). Animals subjected to AAC during the non-proliferative heart growth (AAC-PD6) and Sham-operated rats served as controls. Electrical remodeling was assessed at PD21 using ECG, optical mapping, western blots, immunofluorescence, and lipidomic analysis, complemented by functional analyses through echocardiography.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pressure overload led to a 2.5-fold increase in heart weight compared to Sham in both AAC groups. A significant increase in relative left ventricular wall thickening was observed in AAC-PD2 rats only. Optical mapping and ECG showed preserved conduction properties in AAC-PD2 animals, whereas the AAC-PD6 group displayed prolonged QRS and significantly reduced longitudinal CV. While total and phosphorylated Cx43 levels were comparable between the AAC groups, AAC-PD2 animals demonstrated higher intercalated disc localization. Furthermore, lipidomic profiling revealed maintained long-chain acylcarnitine (LCAC) levels in AAC-PD2, whereas AAC-PD6 tended toward LCAC accumulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study provides new insights into the remodeling upon pressure overload during cardiac proliferative growth, demonstrating attenuated electrical alteration by preserved CV and highlighting the role of Cx43 localization and preserved levels of LCACs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Riley R. Parks, Marissa J. Andersen, Mackenna L. Hatfield, Nicholas J. Burgraff
Aim
Opioid-induced respiratory depression (OIRD) is the primary cause of death in opioid overdose, resulting from both suppressed respiratory rhythm and increased airway and thoracic rigidity that compromise ventilation and resuscitation. While the effect(s) of opioids on central rhythm-generating circuits are well documented, the mechanisms leading to airway obstruction remain poorly understood. Here, we investigated the hypothesis that enhanced vagal parasympathetic output contributes to fentanyl-induced airway disruption.
Methods
In urethane-anesthetized mice, diaphragm electromyography (EMG), respiratory airflow, and vagus nerve activity were recorded in-vivo before and after intraperitoneal fentanyl administration (500 μg/kg). The effects of bilateral vagotomy, atropine administration, and intracisternal naloxone were evaluated to determine the contribution of vagal pathways and central opioid receptor mechanisms.
Results
Fentanyl caused a characteristic slowing of respiratory rate accompanied by a compensatory increase in tidal volume, but also produced a transient delay between diaphragm activation and airflow onset, consistent with airway obstruction. This delay was abolished by bilateral vagotomy or atropine and reversed by intracisternal naloxone, implicating central vagal mechanisms. Vagal electroneurograms showed increased tonic multiunit activity and enhanced large-amplitude single-unit firing, particularly within efferent fibers, together with a loss of normal inspiratory phase-locking. The magnitude of tonic vagal activation strongly correlated with the severity of airway disruption.
Conclusions
Fentanyl disrupts respiratory-autonomic integration by enhancing parasympathetic vagal drive, producing a central, opioid receptor-mediated mechanism of airway constriction. Targeting vagal pathways may therefore represent a promising adjunctive strategy for improving airway patency and ventilatory recovery during opioid overdose reversal.
{"title":"Fentanyl Disrupts Vagal Control of Airway Tone to Induce Transient Obstruction","authors":"Riley R. Parks, Marissa J. Andersen, Mackenna L. Hatfield, Nicholas J. Burgraff","doi":"10.1111/apha.70119","DOIUrl":"10.1111/apha.70119","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Opioid-induced respiratory depression (OIRD) is the primary cause of death in opioid overdose, resulting from both suppressed respiratory rhythm and increased airway and thoracic rigidity that compromise ventilation and resuscitation. While the effect(s) of opioids on central rhythm-generating circuits are well documented, the mechanisms leading to airway obstruction remain poorly understood. Here, we investigated the hypothesis that enhanced vagal parasympathetic output contributes to fentanyl-induced airway disruption.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In urethane-anesthetized mice, diaphragm electromyography (EMG), respiratory airflow, and vagus nerve activity were recorded in-vivo before and after intraperitoneal fentanyl administration (500 μg/kg). The effects of bilateral vagotomy, atropine administration, and intracisternal naloxone were evaluated to determine the contribution of vagal pathways and central opioid receptor mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fentanyl caused a characteristic slowing of respiratory rate accompanied by a compensatory increase in tidal volume, but also produced a transient delay between diaphragm activation and airflow onset, consistent with airway obstruction. This delay was abolished by bilateral vagotomy or atropine and reversed by intracisternal naloxone, implicating central vagal mechanisms. Vagal electroneurograms showed increased tonic multiunit activity and enhanced large-amplitude single-unit firing, particularly within efferent fibers, together with a loss of normal inspiratory phase-locking. The magnitude of tonic vagal activation strongly correlated with the severity of airway disruption.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Fentanyl disrupts respiratory-autonomic integration by enhancing parasympathetic vagal drive, producing a central, opioid receptor-mediated mechanism of airway constriction. Targeting vagal pathways may therefore represent a promising adjunctive strategy for improving airway patency and ventilatory recovery during opioid overdose reversal.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12522075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miho Shimari, Gaia Picozzi, Ariela Boeder, Drielle Dantas Guimarães, Zhengbing Zhuge, Jon O. Lundberg, Mattias Carlstrom, Lars H. Lund, Daniel C. Andersson, Gianluigi Pironti
Aims
Impaired cardiac function, reduced nitric oxide (NO) bioavailability, and inflammation are key contributors to the pathogenesis and progression of heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate whether dietary inorganic nitrate supplementation can attenuate cardiac dysfunction and adverse remodeling in HFrEF by enhancing NO signaling.
Methods
Two mouse models of HFrEF, induced by myocardial infarction (MI) or transverse aortic constriction (TAC), were treated with dietary nitrate or a control diet for 4–6 weeks, initiating the treatment on day 3 after myocardial injury. Echocardiography and pressure volume (PV) loop analysis were employed to assess cardiac function and hemodynamics. Histology staining was performed to assess the degree of cardiac fibrosis. Myograph experiments were conducted to assess aortic vasorelaxation. Biomarkers related to hypertrophy, fibrosis, and inflammation were analyzed in cardiac tissues through Q-PCR analysis and immunofluorescence staining.
Results
In HFrEF mice, long-term inorganic nitrate treatment increased systolic and diastolic function, enhanced vascular relaxation, and reduced both replacement and reactive fibrosis. In the nitrate group, cardiac gene expression showed downregulation of hypertrophy-, fibrosis-, and inflammation-related markers, alongside upregulation of anti-inflammatory markers associated with M1-to-M2 macrophage polarization. Immunofluorescence confirmed reduced fibrosis and increased anti-inflammatory protein biomarkers associated with increased serum nitrate and cardiac cGMP levels.
Conclusions
Early initiation of dietary nitrate supplementation after myocardial injury enhances cardiac and vascular function, reduces fibrosis and inflammation, and holds promise as a cardioprotective strategy to reduce the progression of HFrEF through NO-signaling.
{"title":"Dietary Nitrate Prevents Cardiac Dysfunction in HFrEF by Improving Hemodynamics, Ameliorating Remodeling, and Resolving Inflammation","authors":"Miho Shimari, Gaia Picozzi, Ariela Boeder, Drielle Dantas Guimarães, Zhengbing Zhuge, Jon O. Lundberg, Mattias Carlstrom, Lars H. Lund, Daniel C. Andersson, Gianluigi Pironti","doi":"10.1111/apha.70115","DOIUrl":"10.1111/apha.70115","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Impaired cardiac function, reduced nitric oxide (NO) bioavailability, and inflammation are key contributors to the pathogenesis and progression of heart failure with reduced ejection fraction (HFrEF). This study aimed to investigate whether dietary inorganic nitrate supplementation can attenuate cardiac dysfunction and adverse remodeling in HFrEF by enhancing NO signaling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Two mouse models of HFrEF, induced by myocardial infarction (MI) or transverse aortic constriction (TAC), were treated with dietary nitrate or a control diet for 4–6 weeks, initiating the treatment on day 3 after myocardial injury. Echocardiography and pressure volume (PV) loop analysis were employed to assess cardiac function and hemodynamics. Histology staining was performed to assess the degree of cardiac fibrosis. Myograph experiments were conducted to assess aortic vasorelaxation. Biomarkers related to hypertrophy, fibrosis, and inflammation were analyzed in cardiac tissues through Q-PCR analysis and immunofluorescence staining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In HFrEF mice, long-term inorganic nitrate treatment increased systolic and diastolic function, enhanced vascular relaxation, and reduced both replacement and reactive fibrosis. In the nitrate group, cardiac gene expression showed downregulation of hypertrophy-, fibrosis-, and inflammation-related markers, alongside upregulation of anti-inflammatory markers associated with M1-to-M2 macrophage polarization. Immunofluorescence confirmed reduced fibrosis and increased anti-inflammatory protein biomarkers associated with increased serum nitrate and cardiac cGMP levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Early initiation of dietary nitrate supplementation after myocardial injury enhances cardiac and vascular function, reduces fibrosis and inflammation, and holds promise as a cardioprotective strategy to reduce the progression of HFrEF through NO-signaling.</p>\u0000 </section>\u0000 </div>","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"241 11","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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