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Exacerbated cardiac fibrosis induced by β‐adrenergic activation in old mice due to decreased AMPK activity
Author(s) -
Wang Jingjing,
Song Yao,
Li Hao,
Shen Qiang,
Shen Jing,
An Xiangbo,
Wu Jimin,
Zhang Jianshu,
Wu Yug,
Xiao Han,
Zhang Youyi
Publication year - 2016
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12622
Subject(s) - ampk , cardiac fibrosis , fibrosis , endocrinology , medicine , activator (genetics) , protein kinase a , ageing , metformin , knockout mouse , amp activated protein kinase , chemistry , receptor , phosphorylation , diabetes mellitus , biochemistry
Summary Senescent hearts exhibit defective responses to β‐adrenergic receptor (β‐ 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 β‐ AR over‐activation. 10‐week‐old (young) and 18‐month‐old (old) mice were subcutaneously injected with the β‐ 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 β‐arrestin 1, but not β‐arrestin 2, expression, and the effects of ISO on AMPK and β‐arrestin 1 were greater in old mice than in young mice. Similarly, young AMPK α2‐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 β‐arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased β‐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 β‐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 β‐ AR over‐activation.