Endogenously produced adiponectin protects cardiomyocytes from hypertrophy by a PPARgamma-dependent autocrine mechanism.
In experimental animal and cell culture models, activation of peroxisome proliferator-activated receptor (PPAR) gamma in heart has been shown to have beneficial effects on cardiac function and cardiomyocyte physiology. The goal of this study was to identify the signaling pathway by which PPARgamma activation protects cardiomyocytes from the deleterious effects of hypertrophic stimuli. In primary cardiomyocyte cultures, we found that genetic or pharmacological activation of PPARgamma protected cells from cardiac hypertrophy induced by alpha-adrenergic stimulation. Examination of gene expression in these cells revealed a surprising increase in the expression of adiponectin in cardiomyocytes and secretion of the high-molecular-weight form of the hormone into media. Using RNAi to block PPARgamma-induced adiponectin production or adiponectin receptor gene expression, we found that the PPARgamma-mediated anti-hypertrophic effect required cardiomyocyte-produced adiponectin, as well as an intact adiponectin signaling pathway. Furthermore, mice expressing constitutive-active PPARgamma and cardiomyocyte specific adiponectin expression were protected from high-fat diet-induced cardiac hypertrophy and remodeling. These findings demonstrate that functional adiponectin hormone can be produced from the heart and raise the possibility that beneficial effects of PPARgamma activation in heart could be due in part to local production of adiponectin that acts on cardiomyocytes in an autocrine manner.
Amin
Rajesh H
RH
Department of Pathology, Center for Integrative Metabolic & Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Mathews
Suresh T
ST
Alli
Adebisi
A
Leff
Todd
T
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052242:Adiponectin; D004041:Dietary Fats; D047495:PPAR gamma; D012333:RNA, Messenger