Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart.
Quantitative in vitro autoradiography has identified high density ACE and AT(1) receptor binding at sites of cardiac injury in the adult rat, implicating Ang II, generated de novo at these sites (tissue Ang II) in contributing to repair. This hypothesis remains to be tested. In the study reported here we used a time-dependent rat model of cardiac injury wherein plasma levels of renin and Ang II are chronically suppressed by means of continuous treatment with aldosterone (0.75 microg/h) and 1% dietary NaCl. To further address a role for tissue Ang II in tissue repair, we administered oral valsartan (10 mg/kg/day) in combination with aldosterone/NaCl. On days 20 and 30 of each regimen, hearts were examined. In coronal sections, we assessed transcription factor NFkappaB activation (RelA subunit), inflammatory-cell infiltration and appearance of myofibroblasts by immunohistochemistry; mRNA expression of several inflammatory (NFkappaB-related) and fibrogenic (type I collagen) mediators of repair, using quantitative in situ hybridization; and ACE binding density, detected with quantitative in vitro autoradiography. Blood pressure was measured with a tail cuff. Untreated age- and sex-matched rats served as controls. On day 20, we found no evidence of cardiac injury, inflammation, or repair with aldosterone/NaCl treatment, with or without valsartan. In contrast, on day 30 of aldosterone/NaCl treatment, inflammatory cells and alpha-SMA-positive myofibroblasts colocalized with high-density ACE binding and histochemical evidence of fibrillar collagen accumulation at sites of microscopic scarring and perivascular fibrosis of intramyocardial coronary arteries that appeared in both right and left ventricles. The activation of NFkappaB and the increased mRNA expression of ICAM-1, MCP-1, TNF-alpha, TGF-beta(1), PAI-1, and type I collagen were also observed at these sites. Expression of vascular cell adhesion molecule-1 was unchanged. Valsartan significantly reduced (P <.01) the expression of these mediators and attenuated the expression of MCP-1. It reduced microscopic evidence of tissue damage and the extent of fibrosis. Blood pressure was increased in aldosterone-treated rats on days 20 and 30; this increase was suppressed by valsartan. We thus show that in this rat model of long-term aldosterone/NaCl administration, in which circulating Ang II is suppressed, AT(1) receptor-mediated actions of tissue Ang II are involved in regulating the expression of mediators of repair at vascular and nonvascular sites of cardiac injury, thereby implicating autocrine/paracrine properties of tissue Ang II in inflammatory and healing responses.
Sun
Yao
Y
Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA. yasun@utmem.edu
Zhang
Jiakun
J
Lu
Li
L
Bedigian
Martin P
MP
Robinson
Antwon D
AD
Weber
Karl T
KT
D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000096:biosynthesis*; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005355:Fibrosis; D006321:Heart / Q000187:drug effects; D017403:In Situ Hybridization; D007263:Infusions, Parenteral; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D024042:Collagen Type I; D016328:NF-kappa B; D017673:Sodium Chloride, Dietary; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D000068756:Valsartan; D014633:Valine