Regulation of Cardiac Remodelling by Adiponectin in Response to Pressure Overload and Unloading: A Focus on the Extracellular Matrix

Cardiac remodelling, the reorganization of the heart which occurs in response to factors impacting its function, includes remodelling of the extracellular matrix (ECM) and hypertrophic cardiomyocyte growth. Pressure overload (PO) induced remodelling of the ECM is initially considered a compensatory mechanism to maintain myocardial integrity, but is also considered a progressive, negative event increasing myocardial stiffness. Adiponectin, an adipokine inversely correlated with type 2 diabetes and obesity, plays an important role in the adaptive response of the heart in various cardiomyopathies, however, adiponectin signalling leading to ECM regulation remains unclear. The studies presented here investigate the role of adiponectin in regulating cardiac remodelling with a particular focus on the ECM from a physiological and mechanistic perspective. Studies using wild-type (WT) and adiponectin deficient (AdKO) mice showed that PO induced left ventricular (LV) cardiac remodelling is delayed by adiponectin deficiency. The appearance of thick collagen fibres and activation of pro-fibrotic genes (MMPs and TIMPs) is delayed in AdKO mice subjected to PO when compared to WT mice. Cardiac hypertrophy and dysfunction, measured by echocardiography, is similarly delayed in AdKO mice. Furthermore, MEF2 activation determined using MEF2-lacZ reporter mice, is decreased in AdKO mice compared to WT mice following PO. Studies in primary neonatal cardiac fibroblasts identified the APPL1-AMPK signalling axis as the mediator of adiponectin stimulated ECM remodelling through membrane localization of APPL1 and subsequent phosphorylation of AMPK, leading to MT1-MMP re-localization, MMP2 activation, and fibroblast migration. Also, adiponectin pre-treatment inhibited angiotensin II induced fibroblast to myofibroblast differentiation. Furthermore, in primary neonatal cardiomyocytes we identify the hypertrophic regulators Myocyte Enhancing Factor-2 (MEF2) and Atrial Natriuretic Factor (ANF) as downstream targets of adiponectin signalling. Lastly, using an in vivo model of reverse remodeling, we show that myocardial strain and cardiac hypertrophy are regressed following LV unloading. However, regression of cardiac fibrosis was incomplete leading to persistent small fibre fibrosis. Together these studies establish adiponectin as an important regulator of cardiac remodelling via the APPL1-AMPK signalling axis and MEF2 activation. Furthermore, we show that adiponectin deficiency confers protection against PO induced remodelling.