Abstract
Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2 = 0.83) and non-structural (e.g. TGFB3 r2 = 0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFβ signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFβ-induced αSMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p < 0.05) inhibited TGFβ signalling activity. In conclusion, our study identifies CILP1 as a new cardiac matricellular protein interfering with pro-fibrotic TGFβ signalling, and as a novel sensitive marker for cardiac fibrosis.
Highlights
cartilage intermediate layer protein 1 (CILP1) mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment
Expression of CILP1 is highly associated with that of other extracellular matrix (ECM) genes and with genes involved in TGFβ signalling in human cardiac tissue
Our results indicate that CILP1 is a novel matricellular protein involved in ECM remodelling in human heart disease and a sensitive marker for cardiac fibrosis
Summary
CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Recombinant CILP1 inhibited TGFβ-induced αSMA gene and protein expression in cardiac fibroblasts. The cardiac ECM consists of structural proteins like the collagens, and of various non-structural proteins that modulate ECM properties, including connective tissue growth factor (CTGF, CCN2) and Osteonectin[1,3,4] Many of these so-called matricellular proteins were first described to have a function in bone formation and homeostasis and later found to be involved in cardiac disease progression[4]. Transcriptome analyses of mouse hearts after transverse aortic constriction revealed increased expression of cartilage intermediate layer protein 1 (CILP1)[5]. This protein has not been linked to cardiac pathophysiology previously and is only known for its role in cartilage[6,7]. The effect of CILP1 on TGFβ signalling was examined in vitro
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