Published online before print June 14, 2007, doi: 10.1161/CIRCRESAHA.107.149047
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© 2007 American Heart Association, Inc.
Integrative Physiology |
Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling
From the Department of Pediatrics (T.O., J.X., R.A.K., J.M., M.H., M.A.S., A.L., E.W.B., G.W.D., B.J.A., J.R., J.D.M.), University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, Ohio; Department of Medicine (E.W.B., G.W.D.), University of Cincinnati, Ohio; and Cardiovascular Development Group (S.J.C.), Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis.
Correspondence to Jeffery D. Molkentin, Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin{at}cchmc.org
The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn–/– mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn–/– hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn–/– hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.
Key Words: cardiac • signaling • hypertrophy • remodeling • mouse genetics
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