Siyu Xiao, Rui Liang, Emilio Lucero, Bradley K McConnell, Zhishi Chen, Jiang Chang, Stephen Navran, Robert J Schwartz, Dinakar Iyer
Introduction: The adult heart lacks the regenerative capacity to self-repair. Serum response factor (SRF) is essential for heart organogenesis, sarcomerogenesis, and contractility. SRF interacts with co-factors, such as NKX2.5 and GATA4, required for cardiac specified gene activity. ETS factors such as ELK1 interact with SRF and drive cell replication. To weaken SRF interactions with NKX2.5 and GATA4, one mutant, SRF153(A3) named STEMIN, did not bind CArG boxes, yet induced stem cell factors such as NANOG and OCT4, cardiomyocyte dedifferentiation, and cell cycle reentry. The mutant YAP5SA of the Hippo pathway also promotes cardiomyocyte proliferation and growth.
Aim: Infarcted adult mouse hearts were injected with translatable STEMIN and YAP5SA mmRNA to evaluate their clinical potential.
Methods and results: Mice were pulsed one day later with alpha-EDU and then heart sections were DAPI stained. Replicating cells were identified by immuno-staining against members of the DNA replisome pathway that mark entry to S phase of the cell cycle. Echocardiography was used to determine cardiac function following infarcts and mRNA treatment. To monitor cardiac wall repair, microscopic analysis was performed, and the extent of myocardial fibrosis was analyzed for immune cell infiltration. Injections of STEMIN and YAP5SA mmRNA into the left ventricles of infarcted adult mice promoted a greater than 17-fold increase in the DAPI stained and alpha-EDU marked cardiomyocyte nuclei, within a day. We observed de novo expression of phospho-histone H3, ORC2, MCM2, and CLASPIN. Cardiac function was significantly improved by four weeks post-infarct, and fibrosis and immune cell infiltration were diminished in hearts treated with STEMIN and YAP5SA mmRNA than each alone.
Conclusion: STEMIN and YAP5SA mmRNA improved cardiac function and myocardial fibrosis in left ventricles of infarcted adult mice. The combinatorial use of mmRNA encoding STEMIN and YAP5SA has the potential to become a powerful clinical strategy to treat human heart disease.
{"title":"STEMIN and YAP5SA synthetic modified mRNAs regenerate and repair infarcted mouse hearts.","authors":"Siyu Xiao, Rui Liang, Emilio Lucero, Bradley K McConnell, Zhishi Chen, Jiang Chang, Stephen Navran, Robert J Schwartz, Dinakar Iyer","doi":"10.20517/jca.2022.20","DOIUrl":"https://doi.org/10.20517/jca.2022.20","url":null,"abstract":"<p><strong>Introduction: </strong>The adult heart lacks the regenerative capacity to self-repair. Serum response factor (SRF) is essential for heart organogenesis, sarcomerogenesis, and contractility. SRF interacts with co-factors, such as NKX2.5 and GATA4, required for cardiac specified gene activity. ETS factors such as ELK1 interact with SRF and drive cell replication. To weaken SRF interactions with NKX2.5 and GATA4, one mutant, SRF153(A3) named STEMIN, did not bind CArG boxes, yet induced stem cell factors such as NANOG and OCT4, cardiomyocyte dedifferentiation, and cell cycle reentry. The mutant YAP5SA of the Hippo pathway also promotes cardiomyocyte proliferation and growth.</p><p><strong>Aim: </strong>Infarcted adult mouse hearts were injected with translatable STEMIN and YAP5SA mmRNA to evaluate their clinical potential.</p><p><strong>Methods and results: </strong>Mice were pulsed one day later with alpha-EDU and then heart sections were DAPI stained. Replicating cells were identified by immuno-staining against members of the DNA replisome pathway that mark entry to S phase of the cell cycle. Echocardiography was used to determine cardiac function following infarcts and mRNA treatment. To monitor cardiac wall repair, microscopic analysis was performed, and the extent of myocardial fibrosis was analyzed for immune cell infiltration. Injections of STEMIN and YAP5SA mmRNA into the left ventricles of infarcted adult mice promoted a greater than 17-fold increase in the DAPI stained and alpha-EDU marked cardiomyocyte nuclei, within a day. We observed de novo expression of phospho-histone H3, ORC2, MCM2, and CLASPIN. Cardiac function was significantly improved by four weeks post-infarct, and fibrosis and immune cell infiltration were diminished in hearts treated with STEMIN and YAP5SA mmRNA than each alone.</p><p><strong>Conclusion: </strong>STEMIN and YAP5SA mmRNA improved cardiac function and myocardial fibrosis in left ventricles of infarcted adult mice. The combinatorial use of mmRNA encoding STEMIN and YAP5SA has the potential to become a powerful clinical strategy to treat human heart disease.</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/PMC9311335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10717542","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 : 2022-07-01Epub Date: 2022-07-04DOI: 10.20517/jca.2022.24
Junichi Sadoshima
Graphical Abstract
{"title":"Fasting confers stress resistance to skeletal muscle stem cells through non-metabolic actions of β-hydroxybutyrate: implications in cardioprotection and aging.","authors":"Junichi Sadoshima","doi":"10.20517/jca.2022.24","DOIUrl":"https://doi.org/10.20517/jca.2022.24","url":null,"abstract":"Graphical Abstract","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/PMC9311383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40646011","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}
Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit the effect sizes seem to be skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity. Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of the DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span. A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.
{"title":"Genetic basis of cardiovascular aging is at the core of human longevity","authors":"A. Marian","doi":"10.20517/jca.2022.06","DOIUrl":"https://doi.org/10.20517/jca.2022.06","url":null,"abstract":"Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit the effect sizes seem to be skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity. Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of the DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span. A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47476567","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":"Thermophiles reveal the clues to longevity: precise protein synthesis.","authors":"Manisha Deogharia, Priyatansh Gurha","doi":"10.20517/jca.2021.38","DOIUrl":"https://doi.org/10.20517/jca.2021.38","url":null,"abstract":"Graphical Abstract","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10765794","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 : 2022-04-01Epub Date: 2022-03-11DOI: 10.20517/jca.2022.03
Travis B Lear, Toren Finkel
Senescent cell accumulation is increasingly associated with a number of age-related cardiovascular diseases. Now, a new manuscript in Nature Aging suggests that a novel vaccine-based strategy might provide a targeted method to eliminate the senescent cell population.
{"title":"Senolytic vaccination: a new mandate for cardiovascular health?","authors":"Travis B Lear, Toren Finkel","doi":"10.20517/jca.2022.03","DOIUrl":"10.20517/jca.2022.03","url":null,"abstract":"<p><p>Senescent cell accumulation is increasingly associated with a number of age-related cardiovascular diseases. Now, a new manuscript in <i>Nature Aging</i> suggests that a novel vaccine-based strategy might provide a targeted method to eliminate the senescent cell population.</p>","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10769365","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}
The development of novel therapies based on understanding the pathophysiologic basis of disease is a major goal of biomedical research. Despite an explosion in new knowledge on the molecular mechanisms of disease derived from animal model investigations, translation into effective treatment for human patients has been disappointingly slow. Several fundamental problems may explain the translational failures. First, the emphasis on novel and highly significant findings selectively rewards implausible, low-probability observations and high-magnitude effects, providing a biased perspective of the pathophysiology of disease that underappreciates the complexity and redundancy of biological systems. Second, even when a sound targetable mechanism is identified, animal models cannot recapitulate the pathophysiologic heterogeneity of the human disease, and are poor predictors of therapeutic success. Third, traditional classifications of most complex diseases are based primarily on clinical criteria and do not reflect the diverse pathophysiologic mechanisms that may be involved. The development of a flexible and dynamic conceptual paradigm that takes into account the totality of the evidence on the mechanisms of disease, and pathophysiologic stratification of patients to identify subpopulations with distinct pathogenetic mechanisms, are crucial for the development of new therapeutics.
{"title":"Why animal model studies are lost in translation","authors":"N. Frangogiannis","doi":"10.20517/jca.2022.10","DOIUrl":"https://doi.org/10.20517/jca.2022.10","url":null,"abstract":"The development of novel therapies based on understanding the pathophysiologic basis of disease is a major goal of biomedical research. Despite an explosion in new knowledge on the molecular mechanisms of disease derived from animal model investigations, translation into effective treatment for human patients has been disappointingly slow. Several fundamental problems may explain the translational failures. First, the emphasis on novel and highly significant findings selectively rewards implausible, low-probability observations and high-magnitude effects, providing a biased perspective of the pathophysiology of disease that underappreciates the complexity and redundancy of biological systems. Second, even when a sound targetable mechanism is identified, animal models cannot recapitulate the pathophysiologic heterogeneity of the human disease, and are poor predictors of therapeutic success. Third, traditional classifications of most complex diseases are based primarily on clinical criteria and do not reflect the diverse pathophysiologic mechanisms that may be involved. The development of a flexible and dynamic conceptual paradigm that takes into account the totality of the evidence on the mechanisms of disease, and pathophysiologic stratification of patients to identify subpopulations with distinct pathogenetic mechanisms, are crucial for the development of new therapeutics.","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43912389","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}
The Cre-loxP system is a powerful and versatile tool to control site-specific recombination of mammalian genomic DNA. Site-specific Cre recombinase-mediated DNA recombination allows for the conditional control of gene expression within transgenic animals in a tissuespecific manner by employing a promoter known to be expressed specifically in such tissue of interest. More specifically, the gene of interest is flanked (floxed) by two loxP (locus of x-over, P1) sites in the presence of Cre recombinase, which then catalyzes the site-specific recombination of DNA between those loxP sites, leading to tissue-specific gene editing. However, the approach is flawed by the lack of control over the timing of Cre recombinase expression which often parallels the expression of the chosen promoter. Consequently, Cre-
{"title":"Optimization of tamoxifen-induced gene regulation in cardiovascular research","authors":"Abitha Sukumaran, S. Sadayappan","doi":"10.20517/jca.2022.12","DOIUrl":"https://doi.org/10.20517/jca.2022.12","url":null,"abstract":"The Cre-loxP system is a powerful and versatile tool to control site-specific recombination of mammalian genomic DNA. Site-specific Cre recombinase-mediated DNA recombination allows for the conditional control of gene expression within transgenic animals in a tissuespecific manner by employing a promoter known to be expressed specifically in such tissue of interest. More specifically, the gene of interest is flanked (floxed) by two loxP (locus of x-over, P1) sites in the presence of Cre recombinase, which then catalyzes the site-specific recombination of DNA between those loxP sites, leading to tissue-specific gene editing. However, the approach is flawed by the lack of control over the timing of Cre recombinase expression which often parallels the expression of the chosen promoter. Consequently, Cre-","PeriodicalId":75051,"journal":{"name":"The journal of cardiovascular aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41499989","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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