The journal of cardiovascular aging最新文献

{"title":"Long-term efficacy and safety of cardiac genome editing for catecholaminergic polymorphic ventricular tachycardia","authors":"Oliver M. Moore, Yuriana Aguilar-Sánchez, S. Lahiri, M. Hulsurkar, J. Navarro-García, Tarah A. Word, Joshua A. Keefe, Dean Barazi, Elda M. Munivez, Charles T. Moore, Vaidya Parthasarathy, Jaysón M. Davidson, William R. Lagor, So Hyun Park, Gang Bao, Christina Y. Miyake, X.H.T. Wehrens","doi":"10.20517/jca.2023.42","DOIUrl":"https://doi.org/10.20517/jca.2023.42","url":null,"abstract":"Introduction: Heterozygous autosomal-dominant single nucleotide variants in RYR2 account for 60% of cases of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia disorder associated with high mortality rates. CRISPR/Cas9-mediated genome editing is a promising therapeutic approach that can permanently cure the disease by removing the mutant RYR2 allele. However, the safety and long-term efficacy of this strategy have not been established in a relevant disease model.\u0000 Aim: The purpose of this study was to assess whether adeno-associated virus type-9 (AAV9)-mediated somatic genome editing could prevent ventricular arrhythmias by removal of the mutant allele in mice that are heterozygous for Ryr2 variant p.Arg176Gln (R176Q/+).\u0000 Methods and Results: Guide RNA and SaCas9 were delivered using AAV9 vectors injected subcutaneously in 10-day -old mice. At 6 weeks after injection, R176Q/+ mice had a 100% reduction in ventricular arrhythmias compared to controls. When aged to 12 months, injected R176Q/+ mice maintained a 100% reduction in arrhythmia induction. Deep RNA sequencing revealed the formation of insertions/deletions at the target site with minimal off-target editing on the wild-type allele. Consequently, CRISPR/SaCas9 editing resulted in a 45% reduction of total Ryr2 mRNA and a 38% reduction in RyR2 protein. Genome editing was well tolerated based on serial echocardiography, revealing unaltered cardiac function and structure up to 12 months after AAV9 injection.\u0000 Conclusion: Taken together, AAV9-mediated CRISPR/Cas9 genome editing could efficiently disrupt the mutant Ryr2 allele, preventing lethal arrhythmias while preserving normal cardiac function in the R176Q/+ mouse model of CPVT.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"78 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381414","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}

{"title":"Regulators of clonal hematopoiesis and physiological consequences of this condition","authors":"E. Park, Megan A. Evans, Kenneth Walsh","doi":"10.20517/jca.2023.39","DOIUrl":"https://doi.org/10.20517/jca.2023.39","url":null,"abstract":"Clonal hematopoiesis (CH) is a prevalent condition that results from somatic mutations in hematopoietic stem cells. When these mutations occur in “driver” genes, they can potentially confer fitness advantages to the affected cells, leading to a clonal expansion. While most clonal expansions of mutant cells are generally considered to be asymptomatic since they do not impact overall blood cell numbers, CH carriers face long-term risks of all-cause mortality and age-associated diseases, including cardiovascular disease and hematological malignancies. While considerable research has focused on understanding the association between CH and these diseases, less attention has been given to exploring the regulatory factors that contribute to the expansion of the driver gene clone. This review focuses on the association between environmental stressors and inherited genetic risk factors in the context of CH development. A better understanding of how these stressors impact CH development will facilitate mechanistic studies and potentially lead to new therapeutic avenues to treat individuals with this condition.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"27 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139128158","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}

{"title":"Turning back time: effects of young plasma on pan epigenetic clocks and implications for the heart","authors":"Kathleen C. Woulfe, Emma L. Robinson","doi":"10.20517/jca.2023.44","DOIUrl":"https://doi.org/10.20517/jca.2023.44","url":null,"abstract":"","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"33 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139126882","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}

{"title":"Adipose tissue lymphocytes and obesity.","authors":"Feng Gao, Benjamin Litchfield, Huaizhu Wu","doi":"10.20517/jca.2023.38","DOIUrl":"10.20517/jca.2023.38","url":null,"abstract":"<p><p>Obesity is associated with chronic inflammation in adipose tissue (AT), mainly evidenced by infiltration and phenotypic changes of various types of immune cells. Macrophages are the major innate immune cells and represent the predominant immune cell population within AT. Lymphocytes, including T cells and B cells, are adaptive immune cells and constitute another important immune cell population in AT. In obesity, CD8+ effector memory T cells, CD4+ Th1 cells, and B2 cells are increased in AT and promote AT inflammation, while regulatory T cells and Th2 cells, which usually function as immune regulatory or type 2 inflammatory cells, are reduced in AT. Immune cells may regulate the metabolism of adipocytes and other cells through various mechanisms, contributing to the development of metabolic diseases, including insulin resistance and type 2 diabetes. Efforts targeting immune cells and inflammation to prevent and treat obesity-linked metabolic disease have been explored, but have not yielded significant success in clinical studies. This review provides a concise overview of the changes in lymphocyte populations within AT and their potential role in AT inflammation and the regulation of metabolic functions in the context of obesity.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10919906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061510","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}

{"title":"Fueling cardiac myocyte proliferation","authors":"Manisha Deogharia, Priyatansh Gurha","doi":"10.20517/jca.2023.47","DOIUrl":"https://doi.org/10.20517/jca.2023.47","url":null,"abstract":"","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"49 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139125220","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}

{"title":"Nobiletin, a polymethoxylated flavonoid, regulates cell survival via the nuclear receptor RORα in cardiomyocytes","authors":"Yuka Shiheido-Watanabe, J. Sadoshima","doi":"10.20517/jca.2023.46","DOIUrl":"https://doi.org/10.20517/jca.2023.46","url":null,"abstract":"","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"18 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139129877","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}

{"title":"Molecular mechanisms underlying sarcopenia in heart failure","authors":"Cody A. Rutledge","doi":"10.20517/jca.2023.40","DOIUrl":"https://doi.org/10.20517/jca.2023.40","url":null,"abstract":"The loss of skeletal muscle, also known as sarcopenia, is an aging-associated muscle disorder that is disproportionately present in heart failure (HF) patients. HF patients with sarcopenia have poor outcomes compared to the overall HF patient population. The prevalence of sarcopenia in HF is only expected to grow as the global population ages, and novel treatment strategies are needed to improve outcomes in this cohort. Multiple mechanistic pathways have emerged that may explain the increased prevalence of sarcopenia in the HF population, and a better understanding of these pathways may lead to the development of therapies to prevent muscle loss. This review article aims to explore the molecular mechanisms linking sarcopenia and HF, and to discuss treatment strategies aimed at addressing such molecular signals.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"190 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139637992","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}

{"title":"Acetyltransferase in cardiovascular disease and aging.","authors":"Mariko Aoyagi Keller, Michinari Nakamura","doi":"10.20517/jca.2024.21","DOIUrl":"10.20517/jca.2024.21","url":null,"abstract":"<p><p>Acetyltransferases are enzymes that catalyze the transfer of an acetyl group to a substrate, a modification referred to as acetylation. Loss-of-function variants in genes encoding acetyltransferases can lead to congenital disorders, often characterized by intellectual disability and heart and muscle defects. Their activity is influenced by dietary nutrients that alter acetyl coenzyme A levels, a key cofactor. Cardiovascular diseases, including ischemic, hypertensive, and diabetic heart diseases - leading causes of mortality in the elderly - are largely attributed to prolonged lifespan and the growing prevalence of metabolic syndrome. Acetyltransferases thus serve as a crucial link between lifestyle modifications, cardiometabolic disease, and aging through both epigenomic and non-epigenomic mechanisms. In this review, we discuss the roles and relevance of acetyltransferases. While the sirtuin family of deacetylases has been extensively studied in longevity, particularly through fasting-mediated NAD⁺ metabolism, recent research has brought attention to the essential roles of acetyltransferases in health and aging-related pathways, including cell proliferation, DNA damage response, mitochondrial function, inflammation, and senescence. We begin with an overview of acetyltransferases, classifying them by domain structure, including canonical and non-canonical lysine acetyltransferases, N-terminal acetyltransferases, and sialic acid <i>O</i>-acetyltransferases. We then discuss recent advances in understanding acetyltransferase-related pathologies, particularly focusing on cardiovascular disease and aging, and explore their potential therapeutic applications for promoting health in older individuals.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"4 26","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143434478","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}

{"title":"Hypoxia-induced stabilization of HIF2A promotes cardiomyocyte proliferation by attenuating DNA damage.","authors":"Shah R Ali, Ngoc Uyen Nhi Nguyen, Ivan Menendez-Montes, Ching-Cheng Hsu, Waleed Elhelaly, Nicholas T Lam, Shujuan Li, Abdallah Elnwasany, Yuji Nakada, Suwannee Thet, Roger S Y Foo, Hesham A Sadek","doi":"10.20517/jca.2023.43","DOIUrl":"10.20517/jca.2023.43","url":null,"abstract":"<p><strong>Introduction: </strong>Gradual exposure to a chronic hypoxic environment leads to cardiomyocyte proliferation and improved cardiac function in mouse models through a reduction in oxidative DNA damage. However, the upstream transcriptional events that link chronic hypoxia to DNA damage have remained obscure.</p><p><strong>Aim: </strong>We sought to determine whether hypoxia signaling mediated by the hypoxia-inducible factor 1 or 2 (HIF1A or HIF2A) underlies the proliferation phenotype that is induced by chronic hypoxia.</p><p><strong>Methods and results: </strong>We used genetic loss-of-function models using cardiomyocyte-specific HIF1A and HIF2A gene deletions in chronic hypoxia. We additionally characterized a cardiomyocyte-specific HIF2A overexpression mouse model in normoxia during aging and upon injury. We performed transcriptional profiling with RNA-sequencing on cardiac tissue, from which we verified candidates at the protein level. We find that HIF2A - rather than HIF1A - mediates hypoxia-induced cardiomyocyte proliferation. Ectopic, oxygen-insensitive HIF2A expression in cardiomyocytes reveals the cell-autonomous role of HIF2A in cardiomyocyte proliferation. HIF2A overexpression in cardiomyocytes elicits cardiac regeneration and improvement in systolic function after myocardial infarction in adult mice. RNA-sequencing reveals that ectopic HIF2A expression attenuates DNA damage pathways, which was confirmed with immunoblot and immunofluorescence.</p><p><strong>Conclusion: </strong>Our study provides mechanistic insights about a new approach to induce cardiomyocyte renewal and mitigate cardiac injury in the adult mammalian heart. In light of evidence that DNA damage accrues in cardiomyocytes with aging, these findings may help to usher in a new therapeutic approach to overcome such age-related changes and achieve regeneration.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10919901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061762","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}

{"title":"Arriving on time: decoding macrophage involvement in atrial fibrillation.","authors":"Yue Yuan,&nbsp;Na Li","doi":"10.20517/jca.2023.28","DOIUrl":"10.20517/jca.2023.28","url":null,"abstract":"Atrial fibrillation (AF) is the most common arrhythmia in adults, with a rising incidence and prevalence [1] . It is associated with increased risks of stroke, heart failure, and death. The risk of AF is associated with various factors, including aging, structural heart disease, obesity, hypertension, inflammation, and others. Rhythm control and rate control are the primary strategies for managing AF in clinical practice. While the focus of rate control is to slow down the heart rate without necessarily converting the abnormal rhythm to normal sinus rhythm, the more desirable rhythm control is to restore and maintain the normal sinus rhythm by utilizing cardioversion, antiarrhythmic drugs, or catheter ablation. The catheter-based ablation techniques have significantly progressed over the past several decades and generally yield satisfactory immediate results, yet the recurrence of AF remains a persistent challenge. Understanding the mechanisms that lead to AF is crucial for developing novel therapeutic strategies.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10287496","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}