Pub Date : 2024-06-14DOI: 10.1038/s44161-024-00492-2
Stéphanie Debette, Masafumi Ihara
Rare and common variants in HTRA1 are associated with ischemic stroke. Research now sheds light on the underlying genetic architecture and suggests a vasculopathy with a broader phenotypic spectrum. Lower HTRA1 protease activity and circulating levels both predict an increased risk of ischemic stroke and coronary artery disease.
{"title":"Redefining common and rare HTRA1 variants as risk factors for polyvascular disease","authors":"Stéphanie Debette, Masafumi Ihara","doi":"10.1038/s44161-024-00492-2","DOIUrl":"10.1038/s44161-024-00492-2","url":null,"abstract":"Rare and common variants in HTRA1 are associated with ischemic stroke. Research now sheds light on the underlying genetic architecture and suggests a vasculopathy with a broader phenotypic spectrum. Lower HTRA1 protease activity and circulating levels both predict an increased risk of ischemic stroke and coronary artery disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"619-621"},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141343513","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 : 2024-06-14DOI: 10.1038/s44161-024-00493-1
Lingling Zhang, Jacob Elkahal, Tianzhen Wang, Racheli Rimmer, Alexander Genzelinakh, Elad Bassat, Jingkui Wang, Dahlia Perez, David Kain, Daria Lendengolts, Roni Winkler, Hanna Bueno-levy, Kfir Baruch Umansky, David Mishaly, Avraham Shakked, Shoval Miyara, Avital Sarusi-Portuguez, Naomi Goldfinger, Amir Prior, David Morgenstern, Yishai Levin, Yoseph Addadi, Baoguo Li, Varda Rotter, Uriel Katz, Elly M. Tanaka, Valery Krizhanovsky, Rachel Sarig, Eldad Tzahor
Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process. Zhang et al. show that Egr1 regulates transient senescence during neonatal heart regeneration and upon agrin-mediated cardiac repair in adult mice, acting downstream of the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts.
{"title":"Egr1 regulates regenerative senescence and cardiac repair","authors":"Lingling Zhang, Jacob Elkahal, Tianzhen Wang, Racheli Rimmer, Alexander Genzelinakh, Elad Bassat, Jingkui Wang, Dahlia Perez, David Kain, Daria Lendengolts, Roni Winkler, Hanna Bueno-levy, Kfir Baruch Umansky, David Mishaly, Avraham Shakked, Shoval Miyara, Avital Sarusi-Portuguez, Naomi Goldfinger, Amir Prior, David Morgenstern, Yishai Levin, Yoseph Addadi, Baoguo Li, Varda Rotter, Uriel Katz, Elly M. Tanaka, Valery Krizhanovsky, Rachel Sarig, Eldad Tzahor","doi":"10.1038/s44161-024-00493-1","DOIUrl":"10.1038/s44161-024-00493-1","url":null,"abstract":"Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process. Zhang et al. show that Egr1 regulates transient senescence during neonatal heart regeneration and upon agrin-mediated cardiac repair in adult mice, acting downstream of the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 8","pages":"915-932"},"PeriodicalIF":9.4,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141344256","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 : 2024-06-14DOI: 10.1038/s44161-024-00487-z
Daniel Eberhard, Sydney Balkenhol, Andrea Köster, Paula Follert, Eric Upschulte, Philipp Ostermann, Philip Kirschner, Celina Uhlemeyer, Iannis Charnay, Christina Preuss, Sandra Trenkamp, Bengt-Frederik Belgardt, Timo Dickscheid, Irene Esposito, Michael Roden, Eckhard Lammert
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD. Eberhard et al. show that SEMA3A regulates liver sinusoidal endothelial cell fenestrations by signaling through NRP1 and LIMK1, revealing a pathway that connects hyperlipidemia to the development of steatotic liver disease.
{"title":"Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis","authors":"Daniel Eberhard, Sydney Balkenhol, Andrea Köster, Paula Follert, Eric Upschulte, Philipp Ostermann, Philip Kirschner, Celina Uhlemeyer, Iannis Charnay, Christina Preuss, Sandra Trenkamp, Bengt-Frederik Belgardt, Timo Dickscheid, Irene Esposito, Michael Roden, Eckhard Lammert","doi":"10.1038/s44161-024-00487-z","DOIUrl":"10.1038/s44161-024-00487-z","url":null,"abstract":"Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD. Eberhard et al. show that SEMA3A regulates liver sinusoidal endothelial cell fenestrations by signaling through NRP1 and LIMK1, revealing a pathway that connects hyperlipidemia to the development of steatotic liver disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"734-753"},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00487-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141341749","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}
Liver sinusoidal endothelial cells have small pores called fenestrae that allow bidirectional exchange of substrates such as lipids between hepatocytes and blood. New work reveals molecular pathways linking hyperlipidemia to these cells’ loss of fenestrae as a starting point for metabolic dysfunction-associated steatotic liver disease.
{"title":"Loss of fenestrae in liver sinusoidal endothelial cells contributes to MASLD","authors":"Nadia Ciriaci, Pierre-Emmanuel Rautou, Johanne Poisson","doi":"10.1038/s44161-024-00490-4","DOIUrl":"10.1038/s44161-024-00490-4","url":null,"abstract":"Liver sinusoidal endothelial cells have small pores called fenestrae that allow bidirectional exchange of substrates such as lipids between hepatocytes and blood. New work reveals molecular pathways linking hyperlipidemia to these cells’ loss of fenestrae as a starting point for metabolic dysfunction-associated steatotic liver disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"622-624"},"PeriodicalIF":0.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141344582","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 : 2024-06-12DOI: 10.1038/s44161-024-00482-4
Randall S. Carpenter, Maria Maryanovich
Hematopoietic stem cells (HSCs) generate all blood cell lineages responsible for tissue oxygenation, life-long hematopoietic homeostasis and immune protection. In adulthood, HSCs primarily reside in the bone marrow (BM) microenvironment, consisting of diverse cell types that constitute the stem cell ‘niche’. The adaptability of the hematopoietic system is required to respond to the needs of the host, whether to maintain normal physiology or during periods of physical, psychosocial or environmental stress. Hematopoietic homeostasis is achieved by intricate coordination of systemic and local factors that orchestrate the function of HSCs throughout life. However, homeostasis is not a static process; it modulates HSC and progenitor activity in response to circadian rhythms coordinated by the central and peripheral nervous systems, inflammatory cues, metabolites and pathologic conditions. Here, we review local and systemic factors that impact hematopoiesis, focusing on the implications of aging, stress and cardiovascular disease. Carpenter and Maryanovich explore how hematopoietic homeostasis, governed by local niche and systemic mechanisms, is impacted by environmental and immune stressors like stress, sleep patterns, aging and inflammation and examine the implications for cardiovascular diseases.
{"title":"Systemic and local regulation of hematopoietic homeostasis in health and disease","authors":"Randall S. Carpenter, Maria Maryanovich","doi":"10.1038/s44161-024-00482-4","DOIUrl":"10.1038/s44161-024-00482-4","url":null,"abstract":"Hematopoietic stem cells (HSCs) generate all blood cell lineages responsible for tissue oxygenation, life-long hematopoietic homeostasis and immune protection. In adulthood, HSCs primarily reside in the bone marrow (BM) microenvironment, consisting of diverse cell types that constitute the stem cell ‘niche’. The adaptability of the hematopoietic system is required to respond to the needs of the host, whether to maintain normal physiology or during periods of physical, psychosocial or environmental stress. Hematopoietic homeostasis is achieved by intricate coordination of systemic and local factors that orchestrate the function of HSCs throughout life. However, homeostasis is not a static process; it modulates HSC and progenitor activity in response to circadian rhythms coordinated by the central and peripheral nervous systems, inflammatory cues, metabolites and pathologic conditions. Here, we review local and systemic factors that impact hematopoiesis, focusing on the implications of aging, stress and cardiovascular disease. Carpenter and Maryanovich explore how hematopoietic homeostasis, governed by local niche and systemic mechanisms, is impacted by environmental and immune stressors like stress, sleep patterns, aging and inflammation and examine the implications for cardiovascular diseases.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"651-665"},"PeriodicalIF":0.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141351724","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 : 2024-06-11DOI: 10.1038/s44161-024-00479-z
We discover a function of innate immune cells that is important for healing injury: macrophages adopt mural cell roles that are important for restoring blood vessel function and perfusion.
{"title":"Macrophages behave like mural cells to promote healing of ischemic muscle injury","authors":"","doi":"10.1038/s44161-024-00479-z","DOIUrl":"10.1038/s44161-024-00479-z","url":null,"abstract":"We discover a function of innate immune cells that is important for healing injury: macrophages adopt mural cell roles that are important for restoring blood vessel function and perfusion.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"625-626"},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141360025","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 : 2024-06-06DOI: 10.1038/s44161-024-00474-4
Jordi Lambert, Sebnem Oc, Matthew D. Worssam, Daniel Häußler, Charles U. Solomon, Nichola L. Figg, Ruby Baxter, Maria Imaz, James C. K. Taylor, Kirsty Foote, Alison Finigan, Krishnaa T. Mahbubani, Tom R. Webb, Shu Ye, Martin R. Bennett, Achim Krüger, Mikhail Spivakov, Helle F. Jørgensen
Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets. Lambert, Oc et al. reconstruct gene regulatory networks from single-cell transcriptomics and epigenetic profiling, compare mouse and human data, and report previously unrecognized regulators of vascular smooth muscle cell proliferation in disease.
{"title":"Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease","authors":"Jordi Lambert, Sebnem Oc, Matthew D. Worssam, Daniel Häußler, Charles U. Solomon, Nichola L. Figg, Ruby Baxter, Maria Imaz, James C. K. Taylor, Kirsty Foote, Alison Finigan, Krishnaa T. Mahbubani, Tom R. Webb, Shu Ye, Martin R. Bennett, Achim Krüger, Mikhail Spivakov, Helle F. Jørgensen","doi":"10.1038/s44161-024-00474-4","DOIUrl":"10.1038/s44161-024-00474-4","url":null,"abstract":"Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets. Lambert, Oc et al. reconstruct gene regulatory networks from single-cell transcriptomics and epigenetic profiling, compare mouse and human data, and report previously unrecognized regulators of vascular smooth muscle cell proliferation in disease.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"714-733"},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44161-024-00474-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141377420","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 : 2024-06-06DOI: 10.1038/s44161-024-00498-w
Andrea Tavosanis
{"title":"Trimming down with semaglutide improves cardiac health in non-diabetic patients","authors":"Andrea Tavosanis","doi":"10.1038/s44161-024-00498-w","DOIUrl":"10.1038/s44161-024-00498-w","url":null,"abstract":"","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"3 6","pages":"614-614"},"PeriodicalIF":0.0,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141376834","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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