Table 7.
Role of the CCN family of matricellular proteins in heart disease
| Role in cardiac homeostasis | Role in heart disease | |
|---|---|---|
| CCN1 | CCN1 −/− mice die during the embryonic period exhibiting defective vessel formation and large AVSDs. 20% of CCN1 +/− have ostium primum ASDs (294), (295). | CCN1 is rapidly upregulated in experimental models of myocardial infarction and pressure overload hypertrophy. Although in vitro experiments suggest potential effects on inflammatory leukocytes, fibroblasts and cardiomyocytes, the role of CCN1 in cardiac remodeling remains unknown. In a model of autoimmune myocarditis CCN1 overexpression attenuated cardiac inflammation (179), (485), (502), (372). |
| CCN2 | CCN2 −/− mice die minutes after birth due to respiratory failure induced by skeletal abnormalities (204). |
Myocardial infarction: CCN2 is markedly upregulated in the infarcted myocardium; its induction is mediated through angiotensin II and TGF-β/Smad3 signaling. In vitro studies and CCN2 overexpression experiments suggest functions in potentiation of TGF—β signaling, profibrotic and angiogenic actions and pro-survival effects on cardiomyocytes (82), (9), (110), (117), (336), (8). Cardiac hypertrophy and fibrosis: CCN2 is consistently upregulated in models of cardiac hypertrophy and fibrosis. CCN2 may mediate hypertrophic and pro-fibrotic actions potentiating TGF-β-mediated effects. CCN2 overexpression studies suggest that by itself CCN2 is not sufficient to induce fibrosis (205), (134), (476), (473), (10), (501), (344), (41), (475). |
| CCN3 | CCN3 −/− mice exhibit septal hypertrophy, ventricular dilation and ectopic septal calcifications (178). | Not known |
| CCN4 | Not known | Myocardial infarction: CCN4 is upregulated in the infarcted heart. Although in vitro studies suggest that CCN4 stimulates fibroblast proliferation and transduces hypertrophic and pro-survival signals in cardiomyocytes, the in vivo significance of these observations is unclear (101), (464), (465). |
| CCN5 | Not known | Cardiac hypertrophy and fibrosis: CCN5 overexpression inhibits hypertrophy and fibrosis induced by cardiac pressure overload attenuating TGF-β/Smad3 signaling (501). Due to the absence of the CT domain, CCN5 appears to act as a dominant negative form of CCN2. |
| CCN6 | No effects | Not known |