期刊
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
卷 43, 期 11, 页码 1029-1037出版社
WILEY
DOI: 10.1111/1440-1681.12622
关键词
ageing; AMPK; beta-adrenoceptor; beta-arrestin; cardiac fibrosis
资金
- National Science Foundation of China (NSFC) [81030001, 81530009, 81300067]
Senescent hearts exhibit defective responses to beta-adrenergic receptor (beta-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon beta-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the beta-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased beta-arrestin 1, but not beta-arrestin 2, expression, and the effects of ISO on AMPK and beta-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPK alpha 2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and beta-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased beta-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases beta-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon beta-AR over-activation.
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