Heart failure (HF) accounts for approximately 450,000 deaths per year in the US, and is the end result of most pathological cardiac insults. HF is characterized by reduced cardiac contractility and global ventricular remodeling. Cardiac fibrosis (CF) is associated with increased ventricular stiffness, diastolic dysfunction, combined systolic and diastolic dysfunction, arrhythmias, diabetic cardiomyopathy, and impaired coronary blood flow in patients with HF. The detection of extensive fibrosis is predictive of mortality in patients with HF and of the effectiveness of long-term HF therapy. Although CF has traditionally been regarded as a secondary phenomenon, it has also been suggested to play a primary role in the progression of HF. The clinical outcomes of patients with symptomatic severe aortic stenosis undergoing aortic valve replacements correlate with CF severity. In line with this finding, CF, but not left ventricular (LV) ejection fraction, is associated with mortality and sudden cardiac death in patients with non-ischemic dilated cardiomyopathy. Thus, CF is a valid target for the treatment of HF; however, effective anti-CF therapies are currently unavailable. CCN5 is a matricellular protein secreted from cardiac fibroblasts (FBs). Previously we demonstrated that CCN5 gene transfer reversed CF that had formerly been established. This anti-CF effect of CCN5 was associated with the inhibition of the TGF-? signaling pathway, the most well-characterized signaling pathway in fibrosis. Further, CCN5 inhibited endothelial-mesenchymal transition and transdifferentiation of FBs to myofibroblasts (MFBs), the two most critical processes for CF progression. In addition, CCN5 induced apoptosis specifically in MFBs, but not in FBs or cardiomyocytes (CMs). Clearance of MFBs appears to significantly contribute to the reversion of CF. Another beneficial effect of CCN5 gene transfer is the normalization of contractile dysfunction in the failing heart. Previously we demonstrated that miR-25 directly targeted cardiac contractile proteins such as SERCA2a. Furthermore, normalization of SERCA2a through down-regulation of miR-25 improved cardiac contractility in the failing heart. We further demonstrated that FB-derived exosomes reduced CM contractility through delivery of miR-25 to CMs. Intriguingly, CCN5 reduced the amounts of FB-derived exosomes and the miR-25 levels within exosomes, suggesting a novel mechanism underlying the cardioprotective role of CCN5.
We aim to further elucidate the molecular mechanisms underlying the cardioprotective functions of CCN5 and test the potential therapeutic efficacy of CCN5 in a porcine model of HF. Our study will establish a platform for future studies aimed at developing a novel therapeutic modality for HF.
Cardiac fibrosis significantly contributes to the development of heart failure. The work proposed in this grant application takes a new approach of focusing on a novel gene CCN5 that is actively involved in the reversal of cardiac fibrosis. An understanding of the role of CCN5 and the related signaling pathways will help identify targets for future therapeutic efforts.
