Transient ACE‐Inhibitor Treatment Produces Persistent Change in Cardiac Fibroblast Physiology

Abstract

Heart failure is a debilitating illness that is characterized by excessive extracellular matrix (ECM) accumulation. Cardiac fibroblasts maintain homeostasis of collagen production and degradation ‐ a tightly regulated process that is critical for normal heart function. Pathological cardiac fibrosis results from uncontrolled proliferation of fibroblasts and excessive production of ECM proteins including collagens – which may be mediated by reactive oxygen species. The pro‐fibrotic effects are mediated by a differentiated and activated fibroblast phenotype termed a myofibroblast. We have previously shown that angiotensin converting enzyme (ACE) inhibitors induce apoptosis of 30% of cardiac fibroblasts in adult spontaneously hypertensive rats (SHR). In addition, a 10% (p<0.05) reduction in left ventricular mass, compared to untreated control and was accompanied by a 12% (p<0.05) reduction in left ventricular DNA content. Moreover, transient ACE inhibition induces persistent changes that protect against future fibrosis and macrophage infiltration in response to injury. Based on these findings, we hypothesize that cardiac fibroblasts isolated from SHR previously treated with an ACE inhibitor will display a less fibrogenic phenotype than those isolated from control SHR. Adult male SHR were treated for 2 weeks with the ACE inhibitor enalapril (30mg/kg per day, p.o.) or water followed by a 2‐week washout period. Cardiac fibroblast were isolated from left ventricle and cultured to P1. Fibroblasts isolated from SHR previously treated with enalapril secreted significantly higher levels of TGF‐β1 in media (↑30%, p<0.05), and tended to have increased expression of the matricellular protein periostin (↑62%, p=0.052) relative to fibroblasts isolated from untreated SHR. Levels of the pro‐oxidant enzyme NOX2 were not different between treatment groups. Taken together, our data demonstrate that cardiac fibroblasts isolated from SHR that were transiently treated in vivo with an ACE inhibitor are different from those isolated from control SHR hearts. Future studies will further determine the extent to which ECM regulatory proteins differ in cells isolated from ACE inhibitor treated rats, and the response of these cells to an in vitro pro‐fibrotic stimulus. We predict that this altered cell population is primarily responsible for the cardio‐protection that we have shown to persist even after stopping ACE inhibitor treatment.Support or Funding InformationFunding: Springboard Grant, UA College of Medicine – PhoenixThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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