HSF1 deficiency accelerates the transition from pressure overload-induced cardiac hypertrophy to heart failure through endothelial miR-195a-3p-mediated impairment of cardiac angiogenesis
2018
Abstract Heat shock transcription factor 1 (
HSF1) deficiency aggravates cardiac remodeling under
pressure overload. However, the mechanism is still unknown. Here we employed
microRNAarray analysis of the heart tissue of
HSF1-knockout (KO) mice to investigate the potential roles of
microRNAsin
pressure overload-induced cardiac remodeling under HSF-1 deficiency, and the profiles of 478
microRNAsexpressed in the heart tissues of adult
HSF1-KO mice were determined. We found that the expression of 5
microRNAswas over 2-fold higher expressed in heart tissues of
HSF1-KO mice than in those of wild-type (WT) control mice. Of the overexpressed
microRNAs, miR-195a-3p had the highest expression level in
HSF1-null endothelial cells (ECs). Induction with miR-195a-3p in ECs significantly suppressed
CD31and VEGF, promoted AngII-induced EC apoptosis, and impaired capillary-like tube formation. In vivo, the upregulation of miR-195a-3p accentuated cardiac hypertrophy, increased the expression of β-MHC and ANP, and compromised systolic function in mice under
pressure overloadinduced by transverse aortic constriction (TAC). By contrast, antagonism of miR-195a-3p had the opposite effect on
HSF1-KO mice. Further experiments confirmed that AMPKα2 was the direct target of miR-195a-3p. AMPKα2 overexpression rescued the reduction of eNOS and VEGF, and the impairment of angiogenesis that was induced by miR-195a-3p. In addition, upregulation of AMPKα2 in the myocardium of
HSF1-null mice by adenovirus-mediated gene delivery enhanced
CD31, eNOS and VEGF, reduced β-MHC and ANP, alleviated
pressure overload-mediated cardiac hypertrophy and restored cardiac function. Our findings revealed that the upregulation of miR-195a-3p due to
HSF1deficiency impaired cardiac angiogenesis by regulating AMPKα2/VEGF signaling, which disrupted the coordination between the myocardial blood supply and the adaptive hypertrophic response and accelerated the transition from cardiac hypertrophy to heart failure in response to
pressure overload.
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