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CELLULAR AND MOLECULAR

Peroxisome Proliferator-Activated Receptor Activation-Mediated Regulation of Endothelin-1 Production via Nitric Oxide and Protein Kinase C Signaling Pathways in Piglet Cerebral Microvascular Endothelial Cell Culture

Vascular Biology Unit (M.A.Y., R.H.N.), Center for Cardiovascular Diseases (M.A.Y., R.H.N., A.O.O.), College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas

Elevated endothelin (ET)-1 has been implicated in cerebrovascular complications following brain trauma characterized by dysregulation of endothelial nitric oxide synthase (eNOS), protein kinase C (PKC), and cerebral function. Recently, vascular expression of PPAR has been observed and suggested to improve vascular dysfunction. We speculate that activation of PPAR in cerebral microvessels can improve cerebral dysfunction following trauma, and we tested the hypothesis that activation of cerebral endothelial peroxisome proliferator-activated receptor (PPAR) will attenuate ET-1 production via a mechanism involving nitric oxide (NO) and PKC. Phorbol 12-myristate 13-acetate (PMA) (1 µM), bradykinin (BK, 1 µM), angiotensin II (AII, 1 µM), or hemoglobin (Hem, 10 µM) increased ET-1 levels by 24-, 11.4-, 3.6-, or 1.3-fold increasing ET-1 levels from 0.36 ± 0.08 to 8.6 ± 0.8, 4.1 ± 0.7, 1.30 ± 0.1, or 0.47 ± 0.03 fmol/µg protein (p < 0.05), respectively. Clofibrate (10 µM) reduced basal ET-1 from 0.36 ± 0.08 (control) to 0.03 ± 0.01 and blunted vasoactive agent-induced increase to 0.12 ± 0.07 (PMA), 0.6 ± 0.04 (BK), 0.25 ± 0.03 (AII), or 0.12 ± 0.03 (Hem) fM/µg protein (p < 0.05). L-Arginine methyl ester (100 µM) inhibited clofibrate-induced reduction in basal ET-1 production. Clofibrate increased PPAR expression, accompanied by increased NO production and eNOS expression. PKC inhibition by calphostin C (10 µM) blocked these effects, whereas activation by PMA reduced basal PPAR expression. Thus, PPAR activation attenuated ET-1 production by agents that mediate brain injury through mechanisms that probably result from PPAR-induced increase in eNOS expression/NO production and complex PKC signaling pathways. Therefore, PPAR activators can be appropriate therapeutic agents to alleviate cerebrovascular dysfunction following cerebral vasospasm.

Address correspondence to: Dr. Momoh A. Yakubu, Vascular Biology Unit, Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Gray Hall Suite 104, 3100 Cleburne Avenue, Houston, TX 77004. E-mail: yakubu_ma{at}tsu.edu