title: Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response.
abstract: Although increasing evidence indicates that an adipokine adiponectin exerts protective actions on heart, its effects on coronary angiogenesis following pressure overload have not been examined previously. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that adiponectin modulates cardiac remodeling in response to pressure overload through its ability to regulate adaptive angiogenesis. Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). APN-KO mice exhibited greater cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction after TAC surgery compared with WT mice. APN-KO mice also displayed reduced capillary density in the myocardium after TAC, which was accompanied by a significant decrease in expression of vascular endothelial growth factor (VEGF) and phosphorylation of AMP-activated protein kinase (AMPK). Inhibition of AMPK in WT mice resulted in aggravated LV systolic function, attenuated myocardial capillary density and decreased VEGF expression in response to TAC. The adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice. Moreover, adenovirus-mediated VEGF delivery reversed the TAC-induced deficiencies in cardiac microvessel formation and ventricular function observed in the APN-KO mice. In cultured cardiac myocytes, adiponectin treatment stimulated VEGF production, which was inhibited by inactivation of AMPK signaling pathway. Collectively, these data show that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of AMPK-dependent angiogenic regulatory axis.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, MA, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.forename: David R
authors.initials: DR
authors.lastname: Pimentel
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052242:Adiponectin / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D052242:Adiponectin; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases