Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1

Cardiac fibroblasts (CF) are crucial in left ventricular (LV) healing and remodeling after myocardial infarction (MI). They are typically activated into myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) microfilaments and contribute to the formation of contractile and mature collagen scars that minimize the adverse dilatation of infarcted areas. CF predominantly express the alpha 1 catalytic subunit of AMP-activated protein kinase (AMPK alpha 1), while AMPK alpha 2 is the major catalytic isoform in cardiomyocytes. AMPK alpha 2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPK alpha 1 interferes with maladaptative heart responses remains unexplored. In this study, we investigated the role of AMPK alpha 1 in modulating LV dilatation and CF fibrosis during post-MI remodeling. AMPK alpha 1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery. The absence of AMPK alpha 1 was associated with increased CF proliferation in infarcted areas, while expression of the myodifferentiation marker a-SMA was decreased. Faulty maturation of myofibroblasts might derive from severe down-regulation of the non-canonical transforming growth factor-beta1/p38 mitogen-activated protein kinase (TGF-beta 1/p38 MAPK) pathway in KO infarcts. In addition, lysyl oxidase (LOX) protein expression was dramatically reduced in the scar of KO hearts. Although infarct size was similar in AMPK-KO and WT hearts subjected to MI, these changes resulted in compromised scar contractility, defective scar collagen maturation, and exacerbated adverse remodeling, as indicated by increased LV diastolic dimension 30 days after MI. Our data genetically demonstrate the centrality of AMPK alpha 1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology. (C) 2014 Elsevier Ltd. All rights reserved.