Abstract 242: Cardiac Remodeling Induced by Chronic β-Adrenergic Simulation Is Blocked by Myocyte-TGF-β Signaling

Abstract

[Background] Emerging evidence from cell-specific conditional gene manipulation models has revealed complex interactions with differential roles of cardiomyocyte (CM) and non-CM signaling in the evolution of pathological cardiac remodeling. A major factor involved in such cross talk is transforming growth factor-beta (TGFβ), which exists in CM,fibroblasts, and vascular cells. Both mechanical overload and prolonged catecholamine stimulation are critical determinants of hypertensive heart disease. Here, we tested the role of cell-specific TGFβ signaling in chronic pressure-overload or isoproterenol (Iso)-induced cardiac remodeling using CM-specific gene suppression of TGFβ type2 receptor in mice. [Methods and Results] αMHC-driven tamoxifen-inducible Cre (MCM) x Tgfbr2 floxed mice (MCMR2), which achieved CM-specific knockdown of TGFβ signaling, showed a striking suppression of cardiac dilatation and dysfunction induced by chronic pressure-overload. Chronic Iso infusion induced modest cardiac hypertrophy with moderate myocardial fibrosis. Interestingly, in contrast to TAC, myocardial fibrosis induced by the chronic Iso exposure was not inhibited, rather worsened in MCMR2 mice. Systemic treatment with TGFβ neutralizing antibody (NAb) for Chronic Iso significantly inhibited myocardial fibrosis, yet cardiac function and hypertrophy were not improved. In Iso-treated cultured cardiomyocytes, profibrotic genes were up-regulated by TGFβ-receptor inhibition, while they were inhibited in cultured cardiac fibroblasts. [Conclusion] CM-specific TGFβ signaling inhibition has marked protective effect for pressure-overload induced cardiac remodeling but not for Iso-induced cardiac remodeling. These results suggest that the role of TGFβ signaling may be determined by targeted cell types and pathological stresses in a development of heart failure.