Abstract 11396: Myocardial Afadin Attenuates Chronic Pressure Overload-Induced Cardiac Damage via Transforming Growth Factor β Receptor-Mediated Signaling
Afadin, an adaptor protein of cell adhesion molecules nectins, plays a key role in embryonic morphogenesis and tissue organization together with or independent of nectins. However, little is understood how myocardial afadin pathophysiologically functions in the heart. In cardiomyocytes, afadin is reported to localize at the intercalated disks. We, in this study, generated conditional knockout mice lacking myocardial afadin (afadin-cKO mice) by the Cre/loxP system. The proportion of born afadin-cKO mice complied with the Mendel’s law and their appearance was undistinguishable from the littermate control mice. Heart rate, blood pressure, and cardiac dimension and contractility showed similar results between afadin-cKO and control mice. Gross heart morphology, heart weight, histology, and intercalated disks structure in afadin-cKO mice did not differ from those in control mice. We then used a model of chronic pressure overload for 8 weeks created by transverse aortic constriction (TAC) operation. This pressure overload significantly induced systolic dysfunction, enhanced fibrogenesis and apoptosis in afadin-cKO mice comparing with control mice. Myocardial afadin deletion aggravated macrophage infiltration early after TAC procedure. Loss of afadin suppressed transforming growth factor (TGF) β receptor-mediated signaling: phosphorylation of Smad2 and TAK1. Afadin was also found to interact with TGFβ receptor I at the intercalated disks, which was confirmed by co-immunoprecipitation experiments and confocal microscopy. This interaction may contribute to enhancement of TGFβ receptor-mediated signaling initiated by TAC procedure, and prevent cardiac damage. In contrast, administration of SB431542, a pharmacological antagonist of TGFβ receptor I, augmented mononuclear infiltration in the hearts of TAC-operated control mice. In conclusion, afadin is a critical molecule of cardiac protection against chronic pressure overload. The beneficial effects are likely to be a result of afadin interaction with TGFβ receptor.
Author Disclosures: H. Ogita: None. D.P. Zankov: None.
- © 2016 by American Heart Association, Inc.