Regulation of Connective Tissue Growth Factor Gene Expression and Fibrosis in Human Heart Failure

Abstract

Background Heart failure (HF) is associated with excessive extracellular matrix (ECM) deposition and abnormal ECM degradation leading to cardiac fibrosis. Connective Tissue Growth Factor (CTGF) modulates ECM production during inflammatory tissue injury, but available data on CTGF gene expression in failing human heart and its response to mechanical unloading are limited. Methods and Results LV tissue from patients undergoing cardiac transplantation for ischemic (ICM; n=20) and dilated (DCM; n=20) cardiomyopathies, and from nonfailing (NF; n=20) donor hearts were examined. Paired samples (n=15) from patients undergoing LV assist device (LVAD) implantation as “bridge to transplant” (34-1145 days) were also analyzed. There was more interstitial fibrosis in both ICM and DCM compared to NF hearts. Hydroxyproline concentration was also significantly increased in DCM relative to NF samples. The expression of CTGF,TGFB1, COL1-A1, COL3-A1, MMP2 and MMP9 mRNAs in ICM and DCM were also significantly elevated as compared to NF controls. Although TGFB1, CTGF, COL1-A1, and COL3-A1 mRNA levels were reduced by unloading, there was only a modest reduction in tissue fibrosis and no difference in protein-bound hydroxyproline concentration between pre- and post-LVAD tissue samples. The persistent fibrosis may be related to a concomitant reduction in MMP9 mRNA and protein levels following unloading. Conclusions CTGF may be a key regulator of fibrosis during maladaptive remodeling and progression to HF. Although mechanical unloading normalizes most genotypic and functional abnormalities, its effect on ECM remodeling during HF is incomplete.

Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5

“…In contrast to the glycoproteins SPARC and osteopontin, treatment with SM16 did not alter the AB-induced expression of the small proteoglycans decorin and lumican which have been shown to be increased in heart failure and associated with fibrosis [11,29]. As expected, mRNA expression of CTGF, a growth factor suggested to act as a key regulator of cardiac fibrosis [30,31], was increased following AB in this study. Although the present study suggests that the ALK5 inhibitor SM16 attenuated TGF-β induced CTGF expression in CFB in vitro, treatment with SM16 did not alter pressure overload induced LV CTGF mRNA expression in vivo.…”

“…Since the ALK5 inhibitor SM16 did not alter LV CTGF mRNA expression following AB, other signaling pathways independent of ALK5 may be more important for inducing CTGF mRNA in the in vivo setting during pressure overload. Surprisingly, we did not reveal increased mRNA expression of Col1a2 or LOX following stimulation with 1 ng/ml CTGF for 48 h. Although partly supported by one recent report by Gravning et al [32], these results are controversial since several previous studies suggest that CTGF is a pro-fibrotic growth factor [30,31,33,34]. For example, a concentration of 1 ng/ml CTGF has previously been shown to increase collagen content in NRK fibroblasts cultures after 48 h [35], and LOX protein expression in CFB already after 1 h stimulation [34].…”

Transgenic over-expression of YY1 induces pathologic cardiac hypertrophy in a sex-specific manner

“…Fibrosis is associated with cardiac pathology, and collagen 3 expression is increased in the setting of fibrosis [20]. Expression of collagen 3 was analyzed in YY1 transgenic over-expression animals.…”

Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females

“…43 CTGF and Col1 are pro-fibrotic factors that are involved in promoting cardiac stiffness 4, 12 and are increased through TGF-β1/Smad signaling. 4, 12, 42, 44, 45 The WD-induced increase in expression of these matrix/fibrotic proteins was prevented/abrogated by ECMR deletion. To our knowledge, our report is the first to link ECMR to cardiac stiffness.…”