Analyses of differential effects of alpha1 AMPK and alpha2 AMPK on survival and metabolism in cardiac cells

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PanRuping_2014_10_01.pdf (2.18 MB)

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2013

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DOI:
http://dx.doi.org/10.22029/jlupub-14083

Abstract

In the present study, the protective effects of adiponectin-AMPK signaling on mitochondrial biogenesis, apoptosis and cell proliferation in cardiac cells (adult cardiomyocytes, H9C2 cardiomyoblasts) were investigated. The role of alpha1 and alpha2 AMPK in these processes were examined. Adiponectin was able to induce the phosphorylation of AMPK as well as its target ACC in all these cell types. In H9C2 cardiomyoblasts, adiponectin-induced AMPK phosphorylation was mediated by both adipoR1 and adipoR2, and T-cadherin acted as co-receptor for adipoRs. Both AMPK kinases LKB1 and CaMKKbeta were involved in adiponectin-induced AMPK phosphorylation. AMPK phosphorylation either by adiponectin or A-769662 (a pharmacologic agent) showed similar effects on mitochondrial gene expression. In H9C2 cardiomyoblasts, adiponectin increased the enzyme activities of various respiratory chain complexes, which was abolished by AMPK inhibition. With the help of three stable inducible H9C2 cell lines (control, alpha1 AMPK knockdown and alpha2 AMPK knockdown), it was observed that: (1) both alpha1 and alpha2 AMPK were required for the expression and activation of mitochondrial complex I and therefore the mitochondrial respiration via complex I-III respiratory chain, but not complex II-III respiratory chain; (2) and both alpha1 and alpha2 AMPK were required for the expression and activation of mitochondrial complex IV. Furthermore, AMPK activation by either adiponectin or A-769662 showed an anti-apoptotic effect in H9C2 cardiomyoblasts. Alpha2 AMPK deletion resulted in cell apoptosis indicated by lower cell viability and rather higher activities of caspase3/7. Both alpha1 and alpha2 AMPK were required for the proliferation of H9C2 cardiomyoblasts, which was demonstrated by less DNA replication in these AMPK knockdown cells. Data of the present study revealed protective effects of alpha1 and alpha2 AMPK in cardiac cells, which may also suggest an important role of AMPK, as a potential therapeutic target, in the treatment of cardiac diseases.

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