Abstract 15096: Plgf Acts as a Master Regulator of Cardiac Inflammation Upon Pressure Overload, by Controlling TIMP-3/TACE Axis.
Heart failure is the final stage of several overload cardiomyopathies, preceded by an early adaptive hypertrophic response, characterized by coordinated cardiomyocyte growth, angiogenesis and inflammation. Growth factors and cytokines have to be critically regulated during cardiac response to pressure overload. Placental Growth factor (PlGF) shares properties of both angiogenic factor and cytokine and its role in cardiac remodeling is completely unknown. We have induced pressure overload by transverse aortic constriction (TAC) in mice knock-out for PlGF finding that they displayed a dysregulation of cardiac remodeling, impairing muscle growth and leading to early dilated cardiomyopathy and heart failure. The dissection of the dual faces of PlGF, as angiogenic factor and as cytokine, underscored that its role in cardiac pressure overload was mainly ascribable to a failure in establishment of adequate inflammatory response. In particular, we found an impaired activity of TNF-alpha converting enzyme (TACE) and consequent release of TNF-alpha, recruitment of monocytes and development of LV fibrosis. Interestingly, we found that after TAC PlGF KO mice strongly increased mRNA levels of TIMP-3, the main natural TACE inhibitor, in cardiomyocytes and vessels, as shown by in situ hybridization. These results, indicating an unbalance of TIMP-3/TACE axis, prompted us to use an in vivo RNA interference approach to reduce TIMP-3 levels in PlGF KO mice during TAC. Strikingly, we obtained a complete phenotype rescue of early dilated cardiomyopathy and inflammatory response. Overall our results demonstrate that PlGF finely tunes a balanced regulation of TIMP-3/TACE axis, and the consequent TNF-alpha activation, in response to TAC, thus allowing the establishment of an inflammatory response necessary for adaptive cardiac remodeling.
- © 2011 by American Heart Association, Inc.