Pub Date : 2026-02-06DOI: 10.1038/s44161-026-00777-8
Emirhan Celik, Richard T Lee
{"title":"A glucocorticoid brake that unlocks cardiac regeneration via glucocorticoid receptor antagonization.","authors":"Emirhan Celik, Richard T Lee","doi":"10.1038/s44161-026-00777-8","DOIUrl":"https://doi.org/10.1038/s44161-026-00777-8","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133836","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 : 2026-02-06DOI: 10.1038/s44161-026-00776-9
Silvia Da Pra, Stefano Boriati, Carmen Miano, Francesca Sacchi, Christopher Batho, Chiara Bongiovanni, Irene Del Bono, Alla Aharonov, Nicola Pianca, Riccardo Tassinari, Rowda Dahir, Carlo Ventura, Mattia Lauriola, Eldad Tzahor, Catherine H Wilson, Gabriele D'Uva
Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.
{"title":"Harnessing glucocorticoid receptor antagonism to enhance the efficacy of cardiac regenerative growth factors and cytokines.","authors":"Silvia Da Pra, Stefano Boriati, Carmen Miano, Francesca Sacchi, Christopher Batho, Chiara Bongiovanni, Irene Del Bono, Alla Aharonov, Nicola Pianca, Riccardo Tassinari, Rowda Dahir, Carlo Ventura, Mattia Lauriola, Eldad Tzahor, Catherine H Wilson, Gabriele D'Uva","doi":"10.1038/s44161-026-00776-9","DOIUrl":"https://doi.org/10.1038/s44161-026-00776-9","url":null,"abstract":"<p><p>Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.</p>","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133799","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 : 2026-02-05DOI: 10.1038/s44161-026-00783-w
Gerburg Schwaerzer
{"title":"The vagus nerve is a guardian of cardiac youthfulness.","authors":"Gerburg Schwaerzer","doi":"10.1038/s44161-026-00783-w","DOIUrl":"https://doi.org/10.1038/s44161-026-00783-w","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146127740","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 : 2026-02-02DOI: 10.1038/s44161-026-00781-y
Andrea Tavosanis
{"title":"Endothelial ZBTB16 preserves vascular health and cardiac function during aging.","authors":"Andrea Tavosanis","doi":"10.1038/s44161-026-00781-y","DOIUrl":"https://doi.org/10.1038/s44161-026-00781-y","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":" ","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146108895","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 : 2026-01-12DOI: 10.1038/s44161-025-00772-5
Diverse mutations in RPL3L, the muscle-specific paralog of the ribosomal protein RPL3, have been associated with severe infantile dilated cardiomyopathy and often fatal heart failure. We show that disease is primarily driven by hotspot RPL3L variants that simultaneously block ribosome biogenesis and induce unproductive splicing of the RPL3 precursor mRNA, thereby preventing any compensatory effects of the ubiquitously expressed RPL3.
{"title":"Hotspot RPL3L variants drive early onset heart failure through a dual mechanism","authors":"","doi":"10.1038/s44161-025-00772-5","DOIUrl":"10.1038/s44161-025-00772-5","url":null,"abstract":"Diverse mutations in RPL3L, the muscle-specific paralog of the ribosomal protein RPL3, have been associated with severe infantile dilated cardiomyopathy and often fatal heart failure. We show that disease is primarily driven by hotspot RPL3L variants that simultaneously block ribosome biogenesis and induce unproductive splicing of the RPL3 precursor mRNA, thereby preventing any compensatory effects of the ubiquitously expressed RPL3.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"16-17"},"PeriodicalIF":10.8,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145960852","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 : 2026-01-09DOI: 10.1038/s44161-025-00774-3
Elisa Martini
{"title":"Insights from the IVORY trial targeting regulatory T cells in acute coronary syndrome","authors":"Elisa Martini","doi":"10.1038/s44161-025-00774-3","DOIUrl":"10.1038/s44161-025-00774-3","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"7-7"},"PeriodicalIF":10.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145947119","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 : 2026-01-06DOI: 10.1038/s44161-025-00761-8
Michael R. Murphy, Mythily Ganapathi, Esther R. Rotlevi, Teresa M. Lee, Joshua M. Fisher, Megha V. Patel, Parul Jayakar, Amanda Buchanan, Alyssa L. Rippert, Rebecca C. Ahrens-Nicklas, Divya Nair, Shalini S. Nayak, Aakanksha Anand, Anju Shukla, Rajesh K. Soni, Yue Yin, Feiyue Yang, Enrique J. Garcia, Muredach P. Reilly, Wendy K. Chung, Xuebing Wu
The heart uses a muscle-specific ribosome in cardiomyocytes, where the ribosomal protein RPL3 is replaced by its paralog RPL3L. Rare biallelic RPL3L mutations cause fatal neonatal dilated cardiomyopathy, yet the mechanisms that link genotype to heart failure are unclear. Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms. Here we report four additional cases and propose a unifying pathogenetic model by integrating human genetics, patient tissues and isogenic cell models. Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele. Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing. These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development. Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.
{"title":"Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy","authors":"Michael R. Murphy, Mythily Ganapathi, Esther R. Rotlevi, Teresa M. Lee, Joshua M. Fisher, Megha V. Patel, Parul Jayakar, Amanda Buchanan, Alyssa L. Rippert, Rebecca C. Ahrens-Nicklas, Divya Nair, Shalini S. Nayak, Aakanksha Anand, Anju Shukla, Rajesh K. Soni, Yue Yin, Feiyue Yang, Enrique J. Garcia, Muredach P. Reilly, Wendy K. Chung, Xuebing Wu","doi":"10.1038/s44161-025-00761-8","DOIUrl":"10.1038/s44161-025-00761-8","url":null,"abstract":"The heart uses a muscle-specific ribosome in cardiomyocytes, where the ribosomal protein RPL3 is replaced by its paralog RPL3L. Rare biallelic RPL3L mutations cause fatal neonatal dilated cardiomyopathy, yet the mechanisms that link genotype to heart failure are unclear. Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms. Here we report four additional cases and propose a unifying pathogenetic model by integrating human genetics, patient tissues and isogenic cell models. Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele. Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing. These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development. Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"51-66"},"PeriodicalIF":10.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s44161-025-00761-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-05DOI: 10.1038/s44161-025-00762-7
Junichi Saito, Jui M. Dave, Eunate Gallardo-Vara, Nandhini Sadagopan, Inamul Kabir, George Tellides, Robert K. Riemer, Zsolt Urban, Sarah Spiegel, Timothy Hla, Daniel M. Greif
Deficiency of elastin (ELN), the major component of elastic fibers, leads to excess smooth muscle cells (SMCs), which characterizes arterial diseases (for example, supravalvular aortic stenosis (SVAS)) as well as physiological ductus arteriosus (DA) closure. Here we demonstrate that sphingosine kinase 1 (SPHK1) is a key node in these contexts. Sphk1 is the most upregulated transcript in Eln(−/−) aortic SMCs at embryonic day 15.5 when these cells are initially hyperproliferative. The aorta of humans with SVAS also upregulates SPHK1. Reduced ELN increases levels of transcription factor early growth response 1, resulting in increased SPHK1 levels. SMC-specific Sphk1 deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease. Furthermore, treatment with a SPHK1 inhibitor reduces DA SMC accumulation, leading to DA patency in wild-type mice. These findings indicate that inhibiting SPHK1 may be a therapeutic strategy for SVAS and select congenital heart diseases in which patent DA maintains circulation. Saito et al. identify sphingosine kinase 1 as a critical regulator of physiological ductus arteriosus closure and pathological supravalvular aortic stenosis through its role in smooth muscle cell proliferation and propose potential therapeutics.
{"title":"Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization","authors":"Junichi Saito, Jui M. Dave, Eunate Gallardo-Vara, Nandhini Sadagopan, Inamul Kabir, George Tellides, Robert K. Riemer, Zsolt Urban, Sarah Spiegel, Timothy Hla, Daniel M. Greif","doi":"10.1038/s44161-025-00762-7","DOIUrl":"10.1038/s44161-025-00762-7","url":null,"abstract":"Deficiency of elastin (ELN), the major component of elastic fibers, leads to excess smooth muscle cells (SMCs), which characterizes arterial diseases (for example, supravalvular aortic stenosis (SVAS)) as well as physiological ductus arteriosus (DA) closure. Here we demonstrate that sphingosine kinase 1 (SPHK1) is a key node in these contexts. Sphk1 is the most upregulated transcript in Eln(−/−) aortic SMCs at embryonic day 15.5 when these cells are initially hyperproliferative. The aorta of humans with SVAS also upregulates SPHK1. Reduced ELN increases levels of transcription factor early growth response 1, resulting in increased SPHK1 levels. SMC-specific Sphk1 deletion or pharmacological inhibition of SPHK1 attenuates SMC proliferation and mitigates aortic disease. Furthermore, treatment with a SPHK1 inhibitor reduces DA SMC accumulation, leading to DA patency in wild-type mice. These findings indicate that inhibiting SPHK1 may be a therapeutic strategy for SVAS and select congenital heart diseases in which patent DA maintains circulation. Saito et al. identify sphingosine kinase 1 as a critical regulator of physiological ductus arteriosus closure and pathological supravalvular aortic stenosis through its role in smooth muscle cell proliferation and propose potential therapeutics.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"5 1","pages":"34-50"},"PeriodicalIF":10.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907293","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}
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