ALPHA-11 INTEGRIN EXPRESSION IS ASSOCIATED WITH LEFT VENTRICULAR REMODELING: HUMAN AND CORRELATIVE EXPERIMENTAL STUDIES

Abstract

Integrins, transmembrane receptors, have two major functions: 1) cell attachment to the extracellular matrix (ECM) and 2) signal transduction from the ECM to the cell. In the heart, various pathological stimuli induce adverse ECM remodeling, including fibrosis and excess collagen deposition, contributing to heart failure (HF) in the vast majority of patients. Accordingly, collagen fibril-binding integrins expressed by cardiac fibroblasts may contribute to HF. Notably, the α11β1 integrin (α11) is mainly expressed by fibroblasts and binds preferentially to type I collagen fibers. Currently, the role of the α11 in pathological remodeling of the heart is not defined. We examined the association of α11 in human end-stage HF and experimentally-induced HF in mice. In human LV sections obtained from patients with end-stage idiopathic (n = 5) and ischemic (n = 5) HF, qRT-PCR and Western Blot analysis showed varied α11 mRNA and protein expression. α11 expression appeared upregulated and downregulated in ischemic and idiopathic HF relative to control (1.2 ± 0.34 vs. 0.83 ± 0.34, mRNA, 1.4 ± 0.28 vs. 0.87 ± 0.37, protein), respectively, suggesting a unique role in human end-stage HF (Figure 1). We examined α11 in experimental HF. Normal C57 mice were divided into two groups: 1) transverse aortic constriction (TAC; n = 13) and 2) sham (n = 14). At 6 weeks, mice underwent echocardiography and invasive pressure-volume (PV) loop analysis, followed by tissue collection. Six weeks post-operation, TAC animals demonstrated significant structural and functional differences, including LV and myocyte hypertrophy and myocardial fibrosis. Hearts from TAC animals demonstrated upregulated α11 mRNA and protein expression, consistent with the human data (Table 1). To determine the mechanism of α11 regulation, we examined isolated human cardiac fibroblasts. Applied tensile force increased α11 expression, which was regulated by TGF-β/Smad signaling. Analysis of the α11 promoter identified a novel Smad binding element at nt-881 and nt-890. Utilizing a specific inhibitor of Smad3 phosphorylation, SIS3, α11 promoter activity induced by tensile force, was reduced, which blocked the increased expression of α11 (all P < 0.05). α11 expression is increased in both human and experimental HF, and the increased expression is mediated in part by Smad3 signaling. These findings suggest that α11 is involved in a positive feedback loop whereby enhanced ECM production increases α11 expression, which in turn drives further matrix accumulation. This suggests that α11 may be a novel target to reduce cardiac fibrosis in the failing heart.View Large Image Figure ViewerDownload (PPT)