Abstract
Prior treatment with the ACE inhibitor enalapril followed by washout protects against nitric oxide synthase inhibitor (L-NAME) induced fibrosis, cellular proliferation, and cardiac dysfunction. The present study investigated i) whether in vivo L-NAME administration induces a change in cardiac fibroblast phenotype that persists in vitro, ii) whether prior ACE inhibition protects against L-NAME induced changes in cardiac fibroblasts. SHR were divided into 3 groups: Control, L-NAME (C+L: 7d), enalapril+L-NAME (E+L: 14d enalapril + 14d washout + 7d L-NAME). MAP was measured by radiotelemetry (n=5-9), injury assessed by histology (n=6-10), and heart weight to body weight (HW/BW) was determined after 0 or 7 days of L-NAME in C+L and E+L (n=6-10). In separate rats cardiac fibroblasts were isolated after 7 days of L-NAME (C+L, E+L) or placebo (Con) and cultured to passage 1 (n=10-12). Gene expression was measured by quantitative real-time PCR. L-NAME increased MAP in C+L (22±4.1%) and E+L (21±3.6%) rats. Prior enalapril induced a persistent 13% reduction in HW/BW. L-NAME increased heart mass in E+L (7%) but not C+L; however, HW/BW remained 8% lower than C+L at sacrifice. L-NAME induced infarct in 70% of C+L and 40% of E+L hearts. Cardiac fibroblasts demonstrated a significant increase in proliferation rate in C+L, but not E+L, relative to control (C+L: 1.75-fold vs. con; E+L 1.09-fold vs. con). Fibroblasts from C+L hearts tended to have increased Collagen I and III gene expression. Despite hypertension, cardiac injury, and increased HW/BW; fibroblasts isolated from E+L proliferated at the same rate as those from control. In contrast, those isolated from C+L were hyperproliferative with a tendency toward increased capacity for collagen production. It may be that the fibroblast phenotype from E+L hearts would protect against infarct expansion and account, in part, for the previously reported cardioprotection in these rats.
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