I022 Role of heme oxygenase-1 in high blood flow (shear stress)-induced remodeling of rat resistance arteries

Abstract

We have previously shown that high blood flow (HF)-induced remodeling in mesenteric resistance arteries (MRA) failed to occur in aging. Heme oxygenase (HO)-1 is known to be induced by hemodynamic forces in VSM and endothelial cells. The aim of this work was to evaluate: i) the physiological role of HO activity in HF remodeling in MRA, and ii) the effect of systemic HO-1 induction on altered HF remodeling in MRA of aged rats. First-order MRA from 3- and 18-months-old rats were exposed to HF for 2 (young) or 14 days (young and old) by alternate ligation of 2nd-order arteries. I. Outward hypertrophic remodeling in HF arteries of young control rats (increased diameter and medial cross-sectional area) was associated with a profound increase in the expression of HO-1 mRNA two days after the ligation. II. HO inhibition with Sn-protoporphyrin (50 μmol/kg/day, i.p.) significantly inhibited diameter enlargement in HF arteries. III. HO-1 protein was barely detected in MRA from both young and old rats but was markedly increased after treatment with the HO-1 inducer Co-protoporphyrin (CoPP, 5 mg/kg, twice a week, s.c.). In old rats, CoPP decreased mean arterial blood pressure to a level similar to that in young animals (80±2.5 vs 101.5±2 mmHg, compared with untreated old rats) suggesting that CoPP may act as vasodilator. Moreover, HO-1 induction restored HF remodeling in old animals (17±2 vs 3±3 % increase in diameter, and 18440±2192 vs 13805±323μm2 for medial cross-sectional area when compared to HF in control old rats ; pressure=75mmHg). IV. This latter data was supported by the ability of CoPP to restore HF remodeling in eNOS-KO mice. These novel data show the pivotal role of HO activity in HF-induced remodeling in MRA. This likely occurs via its action on diameter enlargement in parallel with MMPs-dependent matrix degradation, downstream eNOS. Thus, selective HO-1 induction can be used as a new therapeutic approach to ameliorate the prognosis of cardiovascular injury associated with altered adaptation capacity of small arteries to chronic changes in local blood flow such as in ischemic and metabolic diseases or in hypertension, more frequent in the elderly.