Abstract 17481: Cardiomyocyte, Non-Canonical TGFβ Signaling Determines the Pathological Remodeling in Chronic Pressure-Overloaded Heart
Background: Transforming growth factor-beta (TGFβ) has been shown to be involved with cardiac pathological remodeling on a wide array of cellular process. TGFβ works via a canonical pathway, binding to type2 receptor (R2) to activate type1 receptor (R1) and subsequently Smad transcription factors (notably Smad2/3). A non-canonical pathway has also been proposed, coupled to TGFβ-activated kinase (TAK-1). Here, we tested the role of cell-specific TGFβ signaling in pressure-overload cardiac remodeling, contrasting antibody-based inhibition versus CM-specific gene suppression of R2 or R1.
Methods and Results: In mice exposed to 10-wk transverse aortic constriction (TAC), systemic injection of TGFβ neutralizing antibody (NAb) inhibited total cardiac Smad3 activation, yet cardiac function worsened and left ventricle dilated. NAb treatment markedly reduced both perivascular and interstitial fibrosis, whereas hypertrophy (heart weight and cardiomyocyte cross-sectional area) was unaltered. Importantly, while non-CM Smad3 was inhibited, CM Smad3 remained activated. To test if myocyte TGFb activation was more protective, αMHC-driven tamoxifen-inducible Cre (MCM) x Tgfbr2 floxed mice (MCMR2) and Tgfbr1 floxed (MCMR1) mice were generated. Although MCMR1 mice and MCM/no floxed controls had progressive dilatation and dysfunction, the same TAC exposure led to a striking suppression of cardiac dilatation and dysfunction in MCMR2. Pressure-volume analysis confirmed improved function only in MCMR2 despite identical afterload. CM hypertrophy and interstitial fiborsis were less in MCMR2 over MCM/no flx and MCMR1, though perivascular fibrosis was unaltered. CM Smad3 activation declined in both MCMR2 and MCMR1, supporting a key role for Smad-independent signaling. TAC-mediated TAK1 autophosphorylation, a marker of TAK1 activation, was indeed markedly blunted in MCMR2 but not MCMR1 mice.
Conclusion: CM-specific R2 suppression potently blocks pathological remodeling to TAC. Comparisons among NAb treatment, R1 and R2 knockdown supports a key pathologic role for CM over non-CM TGFβ stimulation in pressure-overload, and identifies the importance ofnon-Smad dependent signaling to maladaptive remodeling.
- © 2010 by American Heart Association, Inc.