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Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

ABSTRACT: Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.

SUBMITTER: Bar C

PROVIDER: S-EPMC4871230 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

Bär Christian C Bernardes de Jesus Bruno B Serrano Rosa R Tejera Agueda A Ayuso Eduard E Jimenez Veronica V Formentini Ivan I Bobadilla Maria M Mizrahi Jacques J de Martino Alba A Gomez Gonzalo G Pisano David D Mulero Francisca F Wollert Kai C KC Bosch Fatima F Blasco Maria A MA

Nature communications 20141218

Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses ...[more]

PMID: 25519492

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Project description:Rationale: Ischemic heart disease remains a primary threat to human health, while its precise etiopathogenesis is still unclear. TBC domain family member 15 (TBC1D15) is a RAB7 GTPase-activating protein participating in the regulation of mitochondrial dynamics. This study was designed to explore the role of TBC1D15 in acute myocardial infarction (MI)-induced cardiac injury and the possible mechanism(s) involved. Methods: Mitochondria-lysosome interaction was evaluated using transmission electron microscopy and live cell time-lapse imaging. Mitophagy flux was measured by fluorescence and western blotting. Adult mice were transfected with adenoviral TBC1D15 through intra-myocardium injection prior to a 3-day MI procedure. Cardiac morphology and function were evaluated at the levels of whole-heart, cardiomyocytes, intracellular organelles and cell signaling transduction. Results: Our results revealed downregulated level of TBC1D15, reduced systolic function, overt infarct area and myocardial interstitial fibrosis, elevated cardiomyocyte apoptosis and mitochondrial damage 3 days after MI. Overexpression of TBC1D15 restored cardiac systolic function, alleviated infarct area and myocardial interstitial fibrosis, reduced cardiomyocyte apoptosis and mitochondrial damage although TBC1D15 itself did not exert any myocardial effect in the absence of MI. Further examination revealed that 3-day MI-induced accumulation of damaged mitochondria was associated with blockade of mitochondrial clearance because of enlarged defective lysosomes and subsequent interrupted mitophagy flux, which were attenuated by TBC1D15 overexpression. Mechanistic studies showed that 3-day MI provoked abnormal mitochondria-lysosome contacts, leading to lysosomal enlargement and subsequently disabled lysosomal clearance of damaged mitochondria. TBC1D15 loosened the abnormal mitochondria-lysosome contacts through both the Fis1 binding and the RAB7 GAPase-activating domain of TBC1D15, as TBC1D15-dependent beneficial responses were reversed by interference with either of these two domains both in vitro and in vivo. Conclusions: Our findings indicated a pivotal role of TBC1D15 in acute MI-induced cardiac anomalies through Fis1/RAB7 regulated mitochondria-lysosome contacts and subsequent lysosome-dependent mitophagy flux activation, which may provide a new target in the clinical treatment of acute MI.

Dataset Information

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

Publications

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

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