Adiponectin Mediated APPL1-AMPK Signaling Induces Cell Migration, MMP Activation, and Collagen Remodeling in Cardiac Fibroblasts

Abstract

Defects in adiponectin action have been implicated in the development of cardiac dysfunction in obesity and diabetes. Cardiac fibroblasts play an important role in regulating extracellular matrix remodeling yet little is known regarding the direct effects of adiponectin on cardiac fibroblasts. In this study, we first demonstrated temporal relocalization of cellular APPL1 in response to adiponectin in primary cardiac fibroblasts and that siRNA-mediated knockdown of APPL1 attenuated stimulation of AMPK by adiponectin. The cell surface content of MT1-MMP and activation of MMP2 were induced by adiponectin and these responses were dependent on AMPK signaling. Enhanced MMP activity facilitated increased fibroblast migration in response to adiponectin which was also prevented by inhibition of AMPK, with no change in cell proliferation observed. Collagen and elastin immunofluorescence demonstrated reorganization of the extracellular matrix in accordance with increased MMP activity, whereas quantitative mRNA analysis, (3) H-proline incorporation and picrosirius red assays showed no change in intracellular or extracellular total collagen levels in response to adiponectin. In summary, these data are the first to report the adiponectin stimulated APPL1-AMPK signaling axis in cardiac fibroblasts and characterize MT1-MMP translocation, MMP2 activity and cell migration as functional outcomes. These effects may be of significance in heart failure associated with obesity and diabetes.

Adiponectin is required for cardiac MEF2 activation during pressure overload induced hypertrophy

“…In fact, numerous papers by ourselves and others have demonstrated increased collagen accumulation in the myocardium of Ad-KO mice subjected to MTAB. We recently confirmed direct regulation of the extracellular matrix by adiponectin via AMPK signaling [45], and subsequently performed detailed temporal analysis of the development of fibrosis in wt and Ad-KO mice subjected to pressure overload and although Ad-KO mice had a higher basal fibrosis, there was a delayed fibrotic response to pressure overload when compared with wt mice [16]. Second, this and many other studies using Ad-KO mice subjected to pressure overload have primarily used male mice to avoid potential confounding factors due to the estrus cycle.…”

Arterial stiffness is associated with adipokine dysregulation in non-hypertensive obese mice

“…Hypoadiponectinemia has been associated with a decreased arterial elasticity in both hypertensive and diabetic conditions 16,50,57 . Moreover, hypoadiponectinemia is associated with SMC hypertrophy, as well as collagen accumulation 58,59 . Accordingly, we also find a negative correlation between adiponectin levels and collagen type I in our non-hypertensive obese mice, as well as with stiffness index  or PWV.…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…In a model of angiotensin-induced cardiac remodeling, adiponectin exerted anti-fibrotic effects, presumably mediated through Peroxisome proliferator-activated receptor (PPAR)-a activation (113). In vitro studies have demonstrated both fibrogenic and anti-fibrotic actions of adiponectin on cultured fibroblasts (114), (115); the relevance of these observations in vivo remains unclear. Shibata and co-workers (116) demonstrated that, in db/db mice, exogenous adiponectin attenuated hypertrophic signaling; whether these effects were associated with anti-fibrotic actions has not been systematically investigated.…”