Cardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCM), 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 IGF-1 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 IGF-1 propeptide (mIGF-1) on disease progression in a mouse model of DCM. This mouse model of cardiac-specific and inducible SRF gene disruption mimics some forms of human DCM. Cardiac-specific mIGF-1 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 part of the beneficial effects of mIGF-1 transgene expression were due to counteracting the strong SRF-dependent increase in CTGF expression within cardiomyocytes, 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 heart failure contributes to promote fibrosis and adverse cardiac remodeling. Locally acting mIGF-1 efficiently protects the myocardium from these adverse processes, and may thus represent a cardiac therapeutic avenue to counter DCM.
- Received December 19, 2011.
- Accepted March 29, 2012.
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