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(5)) or SMCs + ECs (10(4)) were incorporated into the gels. To characterize PPAR, agonists of PPAR-alpha [ciprofibrate (CF)] and PPAR-gamma [15-deoxy-12,14-prostaglandin J(2) (PGJ(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 +/- 0.2 mm and was unchanged up to 24 h as measured by a digital micrometer. SMCs reduce gel diameter to 10.5 +/- 0.4 mm at 24 h. Addition of homocysteine to SMCs reduces further the gel diameter to 8.0 +/- 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 +/- 0.3 mm, suggesting that ECs play a role in collagen contraction. Only PGJ(2), not CF, inhibits SMC contraction. However, both PGJ(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.
Mujumdar
Vibhas S
VS
Department of Physiology and Biophysics, School of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Tummalapalli
Chandra M
CM
Aru
Giorgio M
GM
Tyagi
Suresh C
SC
D000970:Antineoplastic Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D016895:Culture Media, Serum-Free; D019483:Disintegrins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D058607:Fibric Acids; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D019483:Disintegrins; D058607:Fibric Acids; D020025:Peroxisome Proliferators; D010975:Platelet Aggregation Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D006710:Homocysteine; D002995:Clofibric Acid; C037112:9-deoxy-delta-9-prostaglandin D2; D003094:Collagen; D008666:Metalloendopeptidases; C019304:ciprofibrate; D015230:Prostaglandin D2