Abstract 20099: Adiponectin Inhibits Maladaptive Cardiac Remodeling in Cardiac Disease by Increasing Matrix Metalloproteinase-9 Activity
Introduction: Adiponectin (APN) is an immunomodulatory adipocytokine that inhibits left ventricular hypertrophy induced by pressure overload as well as hypertension. Here, we investigated whether APN inhibits adverse extracellular matrix (ECM) remodeling in in experimental models of myocardial infarction (MI) and coxsackievirus B3 (CVB3) myocarditis by affecting matrix metalloproteinase (MMP) expression and its possible mechanisms.
Methods: Experimental CVB3 myocarditis and experimental MI were induced in APN-KO and wild-type (WT) C57/BL6J mice. RNA and protein expression/enzymatic activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation status of protein kinases was determined by immunoblot.
Results: In cultured cardiac myocytes and fibroblasts APN induced MMP-9 gene and protein expression by activation of AMPK and MEK1 without affecting MMP-2, MMP-3 and MMP-13. Inhibition with PD098059 and Compound C almost completely abolished MMP-9 up-regulation in this setting. AMPK as well as MEK1 controlled induction of MMP-9 expression by pro-inflammatory stimuli in cardiac fibroblasts. Accordingly, APN further enhanced the increase in MMP-9 expression triggered by TNFα, LPS and R-848 in these cells. Conversely, cardiac fibroblasts from APN-KO mice displayed reduced expression of MMP-9 after stimulation with TNFα, LPS and R-848 ex vivo. In line with these observations, MMP-9 activity was attenuated in hearts and splenocytes of APN-KO mice in subacute CVB3 myocarditis and following MI associated with increased myocardial fibrosis.
Conclusions: Our observations indicate that APN inhibits adverse cardiac remodeling in inflammatory heart disease by inducing MMP-9 expression in resident cardiac and infiltrating immune cells. Persistently enhanced cardiac MMP-9 activity results in increased cleavage of accumulating collagens and augmented ECM turnover thereby attenuating cardiac fibrosis.
Author Disclosures: A.C. Jenke: None. R. Schur: None. L. Holzhauser: None. W. Poller: None. H. Schultheiss: None. C. Skurk: None.
- © 2014 by American Heart Association, Inc.