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
PPARalpha has been observed and suggested to improve vascular dysfunction. We speculate that activation of
PPARalpha in cerebral microvessels can improve cerebral dysfunction following
trauma, and we tested the hypothesis that activation of cerebral endothelial
peroxisome proliferator-activated receptor (
PPAR)alpha will attenuate ET-1 production via a mechanism involving
nitric oxide (NO) and PKC.
Phorbol 12-myristate 13-acetate (PMA) (1 microM),
bradykinin (BK, 1 microM),
angiotensin II (AII, 1 microM), or
hemoglobin (Hem, 10 microM) 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/microg
protein (p < 0.05), respectively.
Clofibrate (10 microM) 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/microg
protein (p < 0.05).
L-arginine methyl ester (100 microM) inhibited
clofibrate-induced reduction in basal ET-1 production.
Clofibrate increased
PPARalpha expression, accompanied by increased NO production and eNOS expression. PKC inhibition by
calphostin C (10 microM) blocked these effects, whereas activation by PMA reduced basal
PPARalpha expression. Thus,
PPARalpha activation attenuated ET-1 production by agents that mediate
brain injury through mechanisms that probably result from
PPARalpha-induced increase in eNOS expression/NO production and complex PKC signaling pathways. Therefore,
PPARalpha activators can be appropriate therapeutic agents to alleviate cerebrovascular dysfunction following
cerebral vasospasm.