0335: Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1

Abstract

Cardiac fibroblasts (CF) are crucial in left ventricular (LV) remodelling after myocardial infarction (MI). They predominantly express the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1), while AMPKα2 is the major catalytic isoform in cardiomyocytes. AMPKα2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPKα1 interferes with maladaptive heart responses remains unexplored. In this study, we aim at further substantiating the role of this AMPK isoform in the pathogenesis of post-MI LV remodelling and more particularly in the regulation of fibrotic properties of CF. AMPKα1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery to mimic MI. Cardiac fibrosis was monitored using qRT-PCR analysis, histology and immunohistofluorescent staining. LV function and remodelling was assessed by echocardiography. In the absence of AMPKα1, the CF proliferative response was increased in infarcted myocardia. It resulted in elevated levels of fibrotic factors but did not lead to excessive matrix deposition or degradation in KO infarcts. While CF proliferation was increased, expression of the myodifferentiation marker a-smooth muscle actin was decreased. This faulty maturation of myofibroblasts might derive from down-regulation of the transforming growth factor-β1/p38 mitogen-activated protein kinase pathway in KO infarcts. Although infarct size was similar in KO and WT hearts subjected to MI, these changes resulted in defective scar collagen maturation. This was associated with an exacerbated adverse remodelling as indicated by increased LV diastolic dimension 30 days after MI. Our data genetically demonstrate the centrality of AMPKα1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology