Abstract 15039: ROCK2-Mediated Fibroblast Growth Factor-2 Expression in Cardiac Fibroblasts is Critical for Inducing Cardiac Hypertrophy and Fibrosis
Introduction: Cardiac hypertrophy and fibrosis can often lead to heart failure. Presently, the pathophysiological mechanism underlying the development of cardiac fibrosis is not known. We hypothesized that Rho-associated coiled-coil containing kinase (ROCK)-2 in cardiac fibroblasts (CFs) may be involved in the pathogenesis of cardiac hypertrophy and fibrosis.
Methods and Results: We developed CF-specific ROCK2-deficient (ROCK2Postn-/-) and CF-specific constitutively active ROCK knockin (caROCKPostn-/-) mice by using fibroblast-specific promoter (Postn) with the Cre/loxP system. Despite comparable increases in systemic blood pressure, angiotensin II (Ang II) infusion (1000ng/kg/min, 28d)-induced cardiac hypertrophy and fibrosis were substantially reduced in ROCK2Postn-/- mice and were enhanced in caROCKPostn-/- mice compared to littermate controls (n=5-10, P<0.05 for each). Consistent with this, the extent of Ang II-induced left ventricular hypertrophy and diastolic dysfunction, as assessed by LV mass and E/A ratio in echocardiography, were attenuated in ROCK2Postn-/- mice and were developed in caROCKPostn-/- mice compared to littermate controls (n=8-10, P<0.05 for each). Following Ang II infusion, the expression of pro-fibrotic (CTGF) and hypertrophic (FGF2) mediators in heart tissues from ROCK2Postn-/- mice was substantially decreased compared to littermate controls (n=5 each, P<0.05 for each). FGF2 caused hypertrophy in H9C2 cardiomyocytes with upregulation of hypertrophic markers (ANF and β-MHC) (n=3 each, P<0.01 for each). Furthermore, TGF-β1-induced increase in intracellular FGF2 expression was absent in ROCK2-deficient MEFs or wild-type MEFs treated with the ROCK inhibitor, Y27632 (n=3, P<0.01 for each). TGF-β1-induced increase in the secreted FGF2 protein in the culture medium was also suppressed in rat neonatal CFs treated with Y27632 (n=3, P<0.05).
Conclusions: These findings indicate that ROCK2 in CF is an important mediator of cardiac hypertrophy and fibrosis through the upregulation of CTGF and FGF2. Inhibition of ROCK2 may prevent the deleterious cardiac remodeling associated with elevated Ang II and TGF-β1 levels.
Author Disclosures: T. Shimizu: None. J.K. Liao: None.
- © 2016 by American Heart Association, Inc.