Abstract 208: Farnesylation-Dependent Fibrosis in the Aged Murine Heart
Mesenchymal stem cells (MSC) derived from the aged murine heart express reduced levels of the multipotency marker Nanog. These CD44+CD45- MSC inappropriately differentiate into fibroblasts characterized by markedly enhanced basal collagen expression. While collagen synthesis in cardiac fibroblasts derived from young mice is driven by TGF-β1, paradoxically, fibroblasts derived from the aged heart displayed reduced TGF-β1 responsiveness and decreased TGF-β receptor expression (ALK5). To resolve this apparent contradiction we looked for other pathways leading to collagen expression. We found that circulating insulin levels in aged mice were elevated ∼2.5 fold when compared to young animals. We hypothesized that increased circulating insulin levels drive MSC differentiation and caused upregulation of procollagen expression in cardiac fibroblasts. Our in vitro experiment confirmed that insulin at a pathophysiological concentration (1 nM) increased procollagen type I expression only in fibroblasts isolated from old hearts. As insulin can signal through substrate prenylation, cardiac fibroblasts isolated from aged mice had ∼2 fold greater basal activity of farnesyltransferase (FTase, enzyme that transfers the prenyl chain) than fibroblasts isolated from young mice. FTase activity was further increased when fibroblasts isolated from aged hearts were stimulated with insulin. Cells derived from 3 month old mice did not upregulate FTase activity in response to insulin. Basal expression of FTase regulatory subunit (FNTA) was also upregulated by 3 fold in aged fibroblasts and expression of catalytic subunit (FTNB) was increased with insulin stimulation. FTase inhibitor reduced procollagen synthesis in aged fibroblasts.
Here we present new data linking insulin-dependent upregulation of collagen type I synthesis via increased farnesylation in the aging heart.
- © 2012 by American Heart Association, Inc.