Abstract 16872: Cardiac Fibrosis Induced by Catecolamine is Paradoxically Controlled by Tgf-beta Signaling
[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 (TGFb), which exists in CM, fibroblasts, and vascular cells. We previously have shown that cardiomyocyte-TGFb signaling has a critical role on pressure-overloaded cardiac remodeling. Here, we tested the role of cell-specific TGFb signaling in isoproterenol (Iso)-induced cardiac remodeling using CM-specific gene suppression of TGFb type2 receptor (Tgfbr2) in mice.
[Methods and Results] We created aMHC-driven tamoxifen-inducible Cre (MCM) x Tgfbr2 floxed mice (MCMR2), which achieved CM-specific knockdown of TGFb signaling. Chronic Iso infusion induces modest cardiac hypertrophy with moderate myocardial fibrosis. In contrast to pressure-overload, cardiac hypertrophy and function were not altered in MCMR2 mice with chronic Iso infusion. Interestingly, myocardial fibrosis induced by the chronic Iso exposure was not inhibited, rather worsened in MCMR2 mice. In vitro study using neonatal rat cardiomyocytes showed that Iso-induced connective tissue growth factor (CTGF) expression was rather enhanced in the presence of TGFb receptor inhibitior, suggesting protective role of TGFb signaling on Iso -induced cardiac fibrosis.
[Conclusion] CM-specific Tgfb signaling inhibition did not have a protective effect for Iso-induced cardiac remodling. These results suggest that cardiomyocyte-TGFb signaling may paradoxically inhibit catecholamine-induced cardiac fibrosis.
- © 2012 by American Heart Association, Inc.