title: 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.
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona.
authors.forename: K M
authors.initials: KM
authors.lastname: D'Souza
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona.
authors.forename: L A
authors.initials: LA
authors.lastname: Biwer
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona.
authors.forename: L
authors.initials: L
authors.lastname: Madhavpeddi
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona.
authors.forename: P
authors.initials: P
authors.lastname: Ramaiah
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona.
authors.forename: W
authors.initials: W
authors.lastname: Shahid
authors.affiliation: Department of Basic Medical Sciences, College of Medicine, University of Arizona, Phoenix, Arizona taben.hale@arizona.edu.
authors.forename: T M
authors.initials: TM
authors.lastname: Hale
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D011918:Rats, Inbred SHR; D013997:Time Factors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D024042:Collagen Type I; D018836:Inflammation Mediators; D004656:Enalapril; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: angiotensin-converting enzyme inhibitor; cardiac fibroblast; collagen; inflammation; proliferation