The journal of cardiovascular aging最新文献

{"title":"Cytosolic DNA sensing protein pathway is activated in human hearts with dilated cardiomyopathy.","authors":"Leila Rouhi, Sirisha M Cheedipudi, Benjamin Cathcart, Priyatansh Gurha, Ali J Marian","doi":"10.20517/jca.2023.20","DOIUrl":"10.20517/jca.2023.20","url":null,"abstract":"<p><strong>Introduction: </strong>The genome is constantly exposed to numerous stressors, which induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates NFκB and IRF3, which induce the expression of the pro-inflammatory genes. There is scant data on the activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM).</p><p><strong>Aim: </strong>We aimed to determine expression levels of selected components of the CDSP pathway in human hearts with DCM.</p><p><strong>Methods: </strong>The DNA strand breaks were detected by the single-cell gel electrophoresis or the comet assay and expression of selected proteins by immunoblotting. Transcript levels were quantified in the RNA-Seq data.</p><p><strong>Results: </strong>Single-cell gel electrophoresis showed an approximately 2-fold increase in the number of COMET cells in the DCM hearts. Immunoblotting showed increased levels of cyclic GMP-AMP synthase (CGAS), the canonical CDSP; TANK-binding kinase 1 (TBK1), an intermediary kinase in the pathway; and RELB, P52, and P50 components of the NFκB pathway in human heart samples from patients with DCM. Likewise, transcript levels of over 2 dozen genes involved in inflammatory responses were increased.</p><p><strong>Conclusions: </strong>The findings provide the first set of evidence for the activation of the CDSP pathway in human hearts with DCM. The data in conjunction with the previous evidence of activation of the DDR pathway implicate the DSBs in the pathogenesis of human DCM.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10352572","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":"Reassessment of genes associated with dilated and hypertrophic cardiomyopathy in a Chinese Han population","authors":"","doi":"10.20517/jca.2022.44","DOIUrl":"https://doi.org/10.20517/jca.2022.44","url":null,"abstract":"","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67657305","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":"Every day is an opportunity to learn something new","authors":"L. Rouhi","doi":"10.20517/jca.2023.05","DOIUrl":"https://doi.org/10.20517/jca.2023.05","url":null,"abstract":"","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67657317","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":"Protein homeostasis in the aged and diseased heart.","authors":"Nirjal Mainali,&nbsp;Srinivas Ayyadevara,&nbsp;Akshatha Ganne,&nbsp;Robert J Shmookler Reis,&nbsp;Jawahar L Mehta","doi":"10.20517/jca.2023.4","DOIUrl":"https://doi.org/10.20517/jca.2023.4","url":null,"abstract":"<p><p>Protein homeostasis, the balance between protein synthesis and degradation, requires the clearance of misfolded and aggregated proteins and is therefore considered to be an essential aspect of establishing a physiologically effective proteome. Aging alters this balance, termed \"proteostasis\", resulting in the progressive accumulation of misfolded and aggregated proteins. Defective proteostasis leads to the functional deterioration of diverse regulatory processes during aging and is implicated in the etiology of multiple pathological conditions underlying a variety of neurodegenerative diseases and in age-dependent cardiovascular disease. Detergent-insoluble protein aggregates have been reported by us in both aged and hypertensive hearts. The protein constituents were found to overlap with protein aggregates seen in neurodegenerative diseases such as Alzheimer's disease. Therefore, targeting these protein components of aggregates may be a promising therapeutic strategy for cardiovascular pathologies associated with aging, ischemia, and/or hypertension.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9758080","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":"Small molecules that enhance mitophagy to delay aging and neurodegeneration.","authors":"Gerald W Dorn","doi":"10.20517/jca.2022.36","DOIUrl":"https://doi.org/10.20517/jca.2022.36","url":null,"abstract":"Mitochondria are central arbiters of cell fate. Mitochondrial respiration produces ATP, the chemical fuel for most biological processes in multicellular organisms. Conversely, mitochondrial respiration that is not properly coupled to ATP synthesis produces mito- and cytotoxic reactive oxygen species (ROS) that can damage cell and organelle DNA, protein and lipid, thereby evoking premature cell senescence or programmed death. The dual role of mitochondria as sustainers of cell life vs engines of cell death requires cells to deploy surveillance and removal systems that identify, isolate and selectively","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9082215","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":"Gut microbiota in sarcopenia and heart failure.","authors":"Chia-Feng Liu,&nbsp;W H Wilson Tang","doi":"10.20517/jca.2022.07","DOIUrl":"https://doi.org/10.20517/jca.2022.07","url":null,"abstract":"<p><p>Sarcopenia is common in aging and in patients with heart failure (HF) who may experience worse outcomes. Patients with muscle wasting are more likely to experience falls and can have serious complications when undergoing cardiac procedures. While intensive nutritional support and exercise rehabilitation can help reverse some of these changes, they are often under-prescribed in a timely manner, and we have limited insights into who would benefit. Mechanistic links between gut microbial metabolites (GMM) have been identified and may contribute to adverse clinical outcomes in patients with cardio-renal diseases and aging. This review will examine the emerging evidence for the influence of the gut microbiome-derived metabolites and notable signaling pathways involved in both sarcopenia and HF, especially those linked to dietary intake and mitochondrial metabolism. This provides a unique opportunity to gain mechanistic and clinical insights into developing novel therapeutic strategies that target these GMM pathways or through tailored nutritional modulation to prevent progressive muscle wasting in elderly patients with heart failure.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40646009","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":"SRF and Yap1, partners in cardiac repair.","authors":"Maha Abdellatif","doi":"10.20517/jca.2022.23","DOIUrl":"https://doi.org/10.20517/jca.2022.23","url":null,"abstract":"Therapeutic strategies for the repair of myocardial ischemic damage are an ongoing challenge for both scientists and clinicians. The obstacle is the limited capacity of the terminally differentiated myocytes to proliferate, mainly due to postnatal downregulation of cell cycle proteins and physical hindrance from the perpetually contracting sarcomeres that occupy most of the cells’ volume. Thus far, some of the strategies employed to undertake this challenge include stem cell implantation or injection, inducing myocyte proliferation, or tissue grafting. However, to date, cardiac ischemic damage remains irreparable. Approaches to induce the myocyte to proliferate include suppressing the cyclin-dependent kinase inhibitors (CDKi) by overexpressing a dominant negative FOXO1 or deletion of Meis1, both of which are known to increase CDKi’s [1] . Alternatively, overexpression of cyclins-CDKs (CDK1, CDK4, cyclin B1, and cyclin D1) partners efficiently enhanced myocyte proliferation, as previously reported by Mohamed et al. [2] . These genes were delivered locally via recombinant adenovirus, which, unfortunately, is unsuitable for gene therapy due to its immunogenicity. Another mechanism involves Yap and TAZ, which activate the transcription of cell cycle proteins, where overexpression of a constitutively active YAP enhances adult myocyte proliferation [3] . Uniquely, Xiao et al., in this issue, combined an SRF153(A3) mutant, STEMIN, which lacks the ability to bind the CArG box, with the cell cycle regulator Yap1 [4] . With this combination, STEMIN induces sarcomere disassembly and dedifferentiation of cardiac myocytes, while YAP increases the expression of the necessary cell cycle proteins, which proved to have a synergestic proliferative effect on the cardiac myocytes. Impressively, intramyocardial injections of the mRNA of both molecules,","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40665393","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":"Hydrogen sulfide: the gas that fuels longevity.","authors":"Erik A Blackwood,&nbsp;Christopher C Glembotski","doi":"10.20517/jca.2022.16","DOIUrl":"https://doi.org/10.20517/jca.2022.16","url":null,"abstract":"<p><p>The molecular determinants of lifespan can be examined in animal models with the long-term objective of applying what is learned to the development of strategies to enhance longevity in humans. Here, we comment on a recent publication examining the molecular mechanisms that determine lifespan in worms, <i>Caenorhabditis elegans</i> (<i>C. elegans</i>), where it was shown that inhibiting protein synthesis increased levels of the transcription factor, ATF4. Gene expression analyses showed that ATF4 increased the expression of genes responsible for the formation of the gas, hydrogen sulfide (H₂S). Further examination showed that H₂S increased longevity in <i>C. elegans</i> by modifying proteins in ways that stabilize their structures and enhance their functions. H₂S has been shown to improve cardiovascular performance in mouse models of heart disease, and clinical trials are underway to test the effects of H₂S on cardiovascular health in humans. These findings support the concept that nutrient deprivation, which slows protein synthesis and leads to ATF4-mediated H₂S production, may extend lifespan by improving the function of the cardiovascular system and other systems that influence longevity in humans.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9259065","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":"Deletion of the <i>Lmna</i> gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype.","authors":"Leila Rouhi,&nbsp;Gaelle Auguste,&nbsp;Qiong Zhou,&nbsp;Raffaella Lombardi,&nbsp;Melis Olcum,&nbsp;Kimia Pourebrahim,&nbsp;Sirisha M Cheedipudi,&nbsp;Saman Asghar,&nbsp;Kui Hong,&nbsp;Matthew J Robertson,&nbsp;Cristian Coarfa,&nbsp;Priyatansh Gurha,&nbsp;Ali J Marian","doi":"10.20517/jca.2022.14","DOIUrl":"https://doi.org/10.20517/jca.2022.14","url":null,"abstract":"<p><strong>Introduction: </strong>Mutations in the <i>LMNA</i> gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts.</p><p><strong>Aim: </strong>The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency.</p><p><strong>Methods and results: </strong>The <i>Lmna</i> gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (<i>Pdgfra-Cre</i>) and floxed <i>Lmna</i> (<i>Lmna</i> ^F/F) mice. The LMNA protein was nearly absent in ~80% of the cardiac fibroblasts and ~25% of cardiac myocytes in the <i>Pdgfra-Cre:Lmna</i> ^F/F mice. The <i>Pdgfra-Cre:Lmna</i> ^F/F mice showed an early phenotype characterized by cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death within the first six weeks of life. The <i>Pdgfra-Cre:Lmna</i> ^{wild type/F} (<i>Lmna</i> ^W/F) mice also showed a similar but slowly evolving phenotype that was expressed within one year of age. RNA sequencing of LMNA-deficient and wild-type cardiac fibroblasts identified differential expression of ~410 genes, which predicted activation of the TP53 and TNFA/NFκB and suppression of the cell cycle pathways. In agreement with these findings, levels of phospho-H2AFX, ATM, phospho-TP53, and CDKN1A, markers of the DNA damage response (DDR) pathway, were increased in the <i>Pdgfra-Cre:Lmna</i> ^F/F mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGFβ1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the <i>Pdgfra-Cre:Lmna</i> ^F/F mouse hearts. Finally, expression of pH2AFX, a bonafide marker of the double-stranded DNA breaks, was increased in cardiac fibroblasts isolated from the <i>Pdgfra-Cre:Lmna</i> ^F/F mouse hearts.</p><p><strong>Conclusion: </strong>Deletion of the <i>Lmna</i> gene in fibroblasts partially recapitulates the phenotype of the LMNA-associated DCM, likely through induction of double-stranded DNA breaks, activation of the DDR pathway, and induction of expression of the SASP proteins. The findings indicate that the phenotype in the LMNA-associated DCM is the aggregate consequence of the LMNA deficiency in multiple cardiac cells, including cardiac fibroblasts.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40646012","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":"Deficient <i>Lmna</i> in fibroblasts: an emerging role of non-cardiomyocytes in DCM.","authors":"Xinjie Wang,&nbsp;Weijia Luo,&nbsp;Jiang Chang","doi":"10.20517/jca.2022.26","DOIUrl":"https://doi.org/10.20517/jca.2022.26","url":null,"abstract":"LMNA gene encodes intermediate filament proteins Lamin A/C. Lamin A and Lamin C polymerize to form nuclear lamina, mainly located in the inner layer of the nuclear envelope. As an essential component of the nuclear envelope, Lamins are necessary for nuclear structural integrity and participate in chromatin organization, cell cycle regulation, and DNA damage response [1] . By far, LMNA has the largest and most","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9450693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33454792","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}