Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-β1 signaling

Feb 14, 2018Journal of molecular and cellular cardiology

Cartilage intermediate layer protein-1 may reduce heart scarring caused by high blood pressure by blocking TGF-β1 signaling

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Abstract

CILP-1 may have an anti-fibrotic role in pressure overload-induced cardiac remodeling.

CILP-1 is primarily produced by cardiac myocytes and is upregulated in response to pressure overload.
Knockdown of CILP-1 worsened while overexpression improved ventricular remodeling and dysfunction in mice subjected to transverse aortic constriction.
CILP-1 inhibited TGF-β1-induced activation of fibrotic pathways in cardiac fibroblasts.
C-terminal CILP-1 enhanced Akt phosphorylation and reduced Smad3 phosphorylation, suggesting a mechanism for its anti-fibrotic effects.
Inhibition of the PI3K-Akt pathway reduced the protective effects of C-terminal CILP-1 on TGF-β1 signaling.

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Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium and results in decreased ventricular compliance and diastolic dysfunction. Cartilage intermediate layer protein-1 (CILP-1), a novel identified cardiac matricellular protein, is upregulated in most conditions associated with cardiac remodeling, however, whether CILP-1 is involved in pressure overload-induced fibrotic response is unknown. Here, we investigated whether CILP-1 was critically involved in the fibrotic remodeling induced by pressure overload. Western blot analysis and immunofluorescence staining showed that CILP-1 was predominantly detected in cardiac myocytes and to a less extent in the interstitium. In isolated adult mouse ventricular myocytes and nonmyocytes, CILP-1 was found to be mainly synthesized by myocytes. CILP-1 expression in left ventricles was upregulated in C57BL/6 mice undergoing transverse aortic constriction (TAC). Myocardial CILP-1 knockdown aggravated whereas CILP-1 overexpression attenuated TAC-induced ventricular remodeling and dysfunction, as measured by echocardiography test, morphological examination, and gene expressions of fibrotic molecules. Incubation of cardiac fibroblasts with the conditioned medium containing full-length, N-terminal, or C-terminal CILP-1 inhibited transforming growth factor (TGF)-β1-induced Smad3 phosphorylation and the subsequent profibrotic events. We first demonstrated that C-terminal CILP-1 increased Akt phosphorylation, promoted the interaction between Akt and Smad3, and suppressed Smad3 phosphorylation. Blockade of PI3K-Akt pathway attenuated the inhibitory effect of C-CILP-1 on TGF-β1-induced Smad3 activation. We conclude that CILP-1 is a novel ECM protein possessing anti-fibrotic ability in pressure overload-induced fibrotic remodeling. This anti-fibrotic effect of CILP-1 attributes to interfering TGF-β1 signaling through its N- and C- terminal fragments.

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Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-β1 signaling

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