sFRP2 activates Wnt/β-catenin signaling in cardiac fibroblasts: differential roles in cell growth, energy metabolism, and extracellular matrix remodeling

Secreted Frizzled-related protein 2 (sFRP2) plays a key role in chronic fibrosis after myocardial infarction and in heart failure. The aim of this study was to elucidate the mechanisms through which sFRP2 may regulate the growth and extracellular matrix (ECM) remodeling of adult mouse cardiac fibroblasts (CFs). We found that sFRP2 activates CFs in part through canonical Wnt/β-catenin signaling, as evidenced by increased expression of Axin2 and Wnt3a, but not Wnt5a, as well as accumulation of nuclear β-catenin. In response to sFRP2, CFs exhibited robust cell proliferation associated with increased glucose consumption and lactate production, a phenomenon termed "the Warburg effect" in oncology. The coupling between CF expansion and anaerobic glycolysis is marked by upregulation of glyceraldehyde-3-phosphate dehydrogenase and tissue-nonspecific alkaline phosphatase. In conjunction with these phenotypic changes, CFs accelerated ECM remodeling through upregulation of expression of the matrix metalloproteinase (MMP) 1 and MMP13 genes, two members of the collagenase subfamily, and enzyme activities of MMP2 and MMP9, two members of the gelatinase subfamily. Consistent with the induction of multiple MMPs possessing collagenolytic activities, the steady-state level of collagen type 1 in CF-spent medium was reduced by sFRP2. Analysis of non-CF cell types revealed that the multifaceted effects of sFRP2 on growth control, glucose metabolism, and ECM regulation are largely restricted to CFs and highly sensitive to Wnt signaling perturbation. The study provides a molecular framework on which the functional versatility and signaling complexity of sFRP2 in cardiac fibrosis may be better defined.