AMP-activated protein kinase α1-sensitive activation of AP-1 in cardiomyocytes

AMP-activated protein kinase (Ampk) regulates myocardial energy metabolism and plays a crucial role in the response to cell stress. In the failing heart, an isoform shift of the predominant Ampk alpha 2 to the Ampk alpha 1 was observed. The present study explored possible isoform specific effects of Ampk alpha 1 in cardiomyocytes. To this end, experiments were performed in HL-1 cardiomyocytes, as well as in Ampk alpha 1-deficient and corresponding wild-type mice and mice following AAV9-mediated cardiac overexpression of constitutively active Ampk alpha 1. As a result, in HL-1 cardiomyocytes, overexpression of constitutively active Ampk alpha 1 increased the phosphorylation of Pkc zeta. Constitutively active Ampkal further increased AP-1-dependent transcriptional activity and mRNA expression of the AP-1 target genes c-Fos, Il6 and Ncx1, effects blunted by Pkc zeta silencing. In HL-1 cardiomyocytes, angiotensin-II activated AP-1, an effect blunted by silencing of Ampk alpha 1 and Pkc zeta, but not of Ampk alpha 2. In wild type mice, angiotensin-II infusion increased cardiac Ampk alpha 1 and cardiac Pkc zeta protein levels, as well as c-Fos, Il6 and Ncx1 mRNA expression, effects blunted in Ampk alpha 1-deficient mice. Pressure overload by transverse aortic constriction (TAC) similarly increased cardiac Ampk alpha 1 and Pkc zeta abundance as well as c-Fos, Il6 and Ncxl mRNA expression, effects again blunted in Ampk alpha 1-deficient mice. AAV9-mediated cardiac overexpression of constitutively active Ampk alpha 1 increased Pkc zeta protein abundance and the mRNA expression of c-Fos, Il6 and Ncx1 in cardiac tissue. In conclusion, Ampk alpha 1 promotes myocardial AP-1 activation in a Pkc zeta-dependent manner and thus contributes to cardiac stress signaling. (C) 2016 Elsevier Ltd. All rights reserved.