| First Author | Noppe G | Year | 2014 |
| Journal | J Mol Cell Cardiol | Volume | 74 |
| Pages | 32-43 | PubMed ID | 24805196 |
| Mgi Jnum | J:225634 | Mgi Id | MGI:5693727 |
| Doi | 10.1016/j.yjmcc.2014.04.018 | Citation | Noppe G, et al. (2014) Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKalpha1. J Mol Cell Cardiol 74:32-43 |
| abstractText | 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 alpha1 catalytic subunit of AMP-activated protein kinase (AMPKalpha1), while AMPKalpha2 is the major catalytic isoform in cardiomyocytes. AMPKalpha2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPKalpha1 interferes with maladaptative heart responses remains unexplored. In this study, we investigated the role of AMPKalpha1 in modulating LV dilatation and CF fibrosis during post-MI remodeling. AMPKalpha1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery. The absence of AMPKalpha1 was associated with increased CF proliferation in infarcted areas, while expression of the myodifferentiation marker alpha-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-beta1/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 30days after MI. Our data genetically demonstrate the centrality of AMPKalpha1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology. |
