Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR

To test the hypothesis that homocysteine induces constrictive vascular remodeling by inactivating peroxisome proliferator-activated receptor (PPAR), aortic endothelial cells (ECs) and smooth muscle cells (SMCs) were isolated. Collagen gels were prepared, and ECs or SMCs ([10.sup.5]) or SMCs + ECs ([10.sup.4]) were incorporated into the gels. To characterize PPAR, agonists of PPAR-[alpha] [ciprofibrate (CF)] and PPAR-[gamma] [15-deoxy-12,14-prostaglandin [J.sub.2] (PG[J.sub.2])] were used. To determine the role of disintegrin metalloproteinase (DMP), cardiac inhibitor of metalloproteinase (CIMP) was used in collagen gels. Gel diameter at 0 h was 14.1 [+ or -] 0.2 mm and was unchanged up to 24 h as measured by a digital micrometer. SMCs reduce gel diameter to 10.5 [+ or -] 0.4 mm at 24 h. Addition of homocysteine to SMCs reduces further the gel diameter to 8.0 [+ or -] 0.2 mm, suggesting that SMCs induce contraction and that the contraction is further enhanced by homocysteine. Addition of ECs and SMCs reduces gel diameter to 12.0 [+ or -] 0.3 mm, suggesting that ECs play a role in collagen contraction. Only PG[J.sub.2], not CF, inhibits SMC contraction. However, both PG[J.sub.2] and CF inhibit contraction of ECs and SMCs + ECs. Addition of anti-DMP blocks SMC- as well as homocysteine-mediated contraction. However, CIMP inhibits only homocysteine-mediated contraction. The results suggest that homocysteine may enhance vascular constrictive remodeling by inactivating PPAR-[alpha] and -[gamma] in ECs and PPAR-[gamma] in SMCs. aorta; arteriosclerosis; hypertension; peroxisome proliferator-activated receptor; fibrate; prostaglandin; endothelial cell; smooth muscle cell