Abstract 1769: Caveolin-1 Regulates TGF-Beta Signaling in Cardiac Remodeling

Abstract

In cardiac fibrosis, fibrous tissue replaces healthy contractile tissue. The regulation of these processes is controlled in large part by transforming growth factor-β (TGF-β). Caveolin-1 (cav1) regulates TGF-β signaling by either sequestering the TGF-β receptor complex or enhancing its degradation. Thus, cav1 may prevent TGF-β directed fibrosis. To investigate the role of cav1 in cardiac remodeling, we performed left ventricular cryoinjury in Cav1-deficient (Cav1−/−) mice and wild-type controls. Ventricular function was followed by echocardiography, and 3, 14, and 30 days after surgery, cardiac RNA and protein were analyzed for inflammatory responses, connective tissue and TGF-β signaling related proteins. Cryoinjured WT presented reduced cav1 expression. Concurrently, evidence of activation of TGF-β signaling was measured as shown by increase of Smad2 phosphorylation. Moreover Cav1−/− cryoinjured hearts had enhanced Smad2 phosphorylation. Collagen gene expression was transiently upregulated in cryoinjured WT mice 3 days post surgery (2.5-fold) and this elevation persisted in Cav1−/− hearts (3.5-fold at 14 days). The level of collagenases (mmp-8 and -13) expression was dramatically increased in the 3-day cryoinjured WT but not in Cav1−/− mice. As a result, augmented collagen deposition, resulting from increased collagen expression and reduced degradation by collagenases, was observed by Masson’s trichrome and picrosirius staining in injured Cav1−/− hearts. WT mice had a transient decline in fractional shortening (FS) but function returned to baseline by 30 days post-injury. In contrast, cryoinjured Cav1−/− mice had a significant lower % FS after 30 days compared to baseline or to cryoinjured WT (67.4 ± 9.6, 76 ± 11, 76.9 ± 5.5, respectively). Moreover Cav1−/− mice presented an altered inflammatory response following cryoinjury. Reduced macrophage infiltrates and IL-6 level of expression were also measured in cryoinjured Cav1−/− mice. These data indicate that in absence of caveolae, TGF-β signaling is enhanced, and this leads to a disordered inflammatory response and suboptimal cardiac remodeling that may impair left ventricular function.