Persistent Phenotypic Shift in Cardiac Fibroblasts Following Transient ACE Inhibition

Abstract

Cardio‐protection afforded by ACE inhibition may be related in part to fibroblast‐specific changes. We have previously shown that transient ACE inhibitor treatment produces long‐term protection against cardiac fibrosis and inflammation in response to myocardial injury induced by L‐NAME. The present study investigates whether transient ACE inhibition produces a persistent phenotypic shift in fibroblasts that may mediate these protective effects. Adult SHR were divided into 3 groups: Control, Control+ L‐NAME (C+L), enalapril (14‐day treatment + 14‐day washout) + L‐NAME (E+L). Cardiac fibroblasts were isolated following in vivo treatment and cultured to passage 1 for measures of macrophage‐recruiting chemokine release, cellular proliferation, and collagen gene expression. In contrast to fibroblasts isolated from C+L, those from E+L rats did not show any increase in Collagen I gene expression, proliferation rate, or release of macrophage‐recruiting chemokines (MCP‐1, GM‐CSF). Our findings demonstrate that prior ACE inhibition resulted in a phenotypic change in fibroblasts to one that resisted L‐NAME‐induced activation. Understanding the mechanism by which ACE inhibition alters fibroblast response to myocardial injury may reveal a novel treatment strategy to prevent pathological cardiac remodeling and ultimate progression to heart failure. Support: Sarver Heart Center