Persistent change in cardiac fibroblast physiology after transient ACE inhibition

Abstract

Transient angiotensin-converting enzyme (ACE) inhibition induces persistent changes that protect against future nitric oxide synthase (NOS) inhibitor-induced cardiac fibrosis and inflammation. Given the role of fibroblasts in mediating these effects, the present study investigates whether prior ACE inhibition produced persistent changes in cardiac fibroblast physiology. Adult male spontaneously hypertensive rats (SHRs) were treated with vehicle (C+L) or the ACE inhibitor, enalapril (E+L) for 2 wk followed by a 2-wk washout period and a subsequent 7-day challenge with the NOS inhibitor N(ω)-nitro-l-arginine methyl ester. A third set of untreated SHRs served as controls. At the end of the study period, cardiac fibroblasts were isolated from control, C+L, and E+L left ventricles to assess proliferation rate, collagen expression, and chemokine release in vitro. After 7 days of NOS inhibition, there were areas of myocardial injury but no significant change in collagen deposition in E+L and C+L hearts in vivo. In vitro, cardiac fibroblasts isolated from C+L but not E+L hearts were hyperproliferative, demonstrated increased collagen type I gene expression, and an elevated secretion of the macrophage-recruiting chemokines monocyte chemoattractant protein-1 and granulocyte macrophage-colony stimulating factor. These findings demonstrate that in vivo N(ω)-nitro-l-arginine methyl ester treatment produces phenotypic changes in fibroblasts that persist in vitro. Moreover, this is the first demonstration that transient ACE inhibition can produce a persistent modification of the cardiac fibroblast phenotype to one that is less inflammatory and fibrogenic. It may be that the cardioprotective effects of ACE inhibition are related in part to beneficial changes in cardiac fibroblast physiology.

Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2

“…Deijanera et al ( 75 ) demonstrated the ACEIs have an effect on reducing TGF-β1, TGF-β2, and Th2 cytokines. ACEIs also induce the apoptosis of cardiac fibroblasts ( 76 ). A clinical trial from Maskito et al ( 77 ) showed the reduction of sST2 in heart failure patients.…”

Transcriptional control of cardiac fibroblast plasticity

“…Further support of this comes from recent data from D'Souza et al, who demonstrate reduced activation in CFs isolated from rats treated with ACE inhibitors. One proposed mechanism is apoptosis of activation-prone CFs and survival of more quiescent CFs [179, 180]. These data suggest that a subpopulation of CFs may retain the ability to revert back into a quiescent state or undergo apoptosis.…”

Functional Gene Module–Based Identification of Phillyrin as an Anticardiac Fibrosis Agent

“…In this study, phillyrin showed effects similar to those of enalapril, further indicating that phillyrin might be a new type of anti-CF agent. Further, in this study, phillyrin was predicted to regulate many genes, including collagen genes, fibrillin, serpin family proteins, laminin, and lysyl oxidase, which are closely related to both fibrosis and inflammation (Van der Donckt et al, 2015;Jeong et al, 2018;Pastel et al, 2018;Choi et al, 2019;Leal-Lopes et al, 2019).…”

“…This study focused on the antifibrotic effect of phillyrin. Enalapril which has an antifibrotic effect was selected as the control medicine in this study ( D’Souza et al., 2015 ; Ham et al., 2018 ). The antifibrotic effect of phillyrin was predicted based on its transcriptional profiles, which was further experimentally validated using animal models.…”