Locally expressed IGF-1 propeptide improves function in induced dilated cardiomyopathy through blockade of myocardial fibrosis and SRF-dependent CTGF induction

Abstract

SUMMARYCardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCMs), which leads to cardiac dysfunction and heart failure (HF). Connective tissue growth factor (CTGF), a profibrotic cytokine, plays a key role in this deleterious process. Some beneficial effects of IGF1 on cardiomyopathy have been described, but its potential role in improving DCM is less well characterized. We investigated the consequences of expressing a cardiac-specific transgene encoding locally acting IGF1 propeptide (muscle-produced IGF1; mIGF1) on disease progression in a mouse model of DCM [cardiac-specific and inducible serum response factor (SRF) gene disruption] that mimics some forms of human DCM. Cardiac-specific mIGF1 expression substantially extended the lifespan of SRF mutant mice, markedly improved cardiac functions, and delayed both DCM and HF. These protective effects were accompanied by an overall improvement in cardiomyocyte architecture and a massive reduction of myocardial fibrosis with a concomitant amelioration of inflammation. At least some of the beneficial effects of mIGF1 transgene expression were due to mIGF1 counteracting the strong increase in CTGF expression within cardiomyocytes caused by SRF deficiency, resulting in the blockade of fibroblast proliferation and related myocardial fibrosis. These findings demonstrate that SRF plays a key role in the modulation of cardiac fibrosis through repression of cardiomyocyte CTGF expression in a paracrine fashion. They also explain how impaired SRF function observed in human HF promotes fibrosis and adverse cardiac remodeling. Locally acting mIGF1 efficiently protects the myocardium from these adverse processes, and might thus represent a therapeutic avenue to counter DCM.

Downregulation of MicroRNA-19b Contributes to Angiotensin II-Induced Overexpression of Connective Tissue Growth Factor in Cardiomyocytes

“…The expression and regulation of CTGF in cardiac fibroblasts have been studied extensively [25]. Cardiomyocytes can also produce CTGF under the stimulation of transforming growth factor-β, endothelin and Ang II [5,26], which would contribute to a paracrine control of cardiac fibroblast functions [27] and regulate the surrounding ECM environment [4,5,28]. Consistent with these findings, our results demonstrated that Ang II can upregulate the expression of CTGF at both mRNA and protein levels.…”

p63RhoGEF regulates auto- and paracrine signaling in cardiac fibroblasts

“…Based on the recent literature [18,36] we hypothesized that the serum response factor (SRF) is involved in the p63RhoGEF-dependent regulation of CTGF. The activation of the SRF was determined by luciferase reporter gene assays in NRCF.…”

“…There is, however, evidence that CTGF is regulated via G protein-coupled receptor activation, and angiotensin II (Ang II) as well as endothelin-1 (ET-1) have been implicated in this process [12][13][14][15][16]. With respect to downstream signaling a role of the actin cytoskeleton regulator RhoA and the serum response factor has been postulated [17,18].…”

Connective tissue growth factor (CTGF) in age-related vascular pathologies

“…In diabetic retinopathy, CTGF contributes to thickening of the retinal capillary basal lamina and is involved in loss of pericytes (Klaassen et al 2015). Interestingly, recent data suggest that downregulation of CTGF via IGF-1 signaling in dilated cardiomyopathy attenuates myocardial fibrosis and improves cardiac function (Touvron et al 2012).…”