NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)α-mediated cardiovascular effects

Activation of peroxisome proliferator activated receptor (PPAR)alpha and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPAR alpha ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPAR alpha activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPAR alpha ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPAR alpha knockout (KO) mice compared with its wild type (WT) litter mates (130 +/- 10 mmHg versus 107 +/- 4 mmHg). L-NAME (100 mg/L p.o.), the inhibitor of NO production abolished the difference between PPAR alpha KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8 +/- 1.4 pM/mg versus 8.3 +/- 0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46 +/- 6%, p < 0.05) and a similar to 3 fold greater Ca2+-dependent NOS activity in kidney homogenates of untreated PPAR alpha WT compared with the KO mice. Clofibrate, a PPAR alpha ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19 +/- 4%, p < 0.05), increased urinary NO excretion (4.06 +/- 0.53-7.07 +/- 1.59 mu M/24 h; p < 0.05) and reduced plasma 8-isoprostane level (45.8 +/- 15 mu M versus 31.4 +/- 8 mu M), and NADP(H) oxidase activity (16 +/- 5%). Implantation of DOCA pellet (20 mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193 +/- 13 mmHg versus 130 12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-I production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-I production, PPAR alpha activation exerts protective actions in hypertension via a mechanism that involves NO production and/or inhibition of NAD(P)H oxidase activity. (c) 2005 Published by Elsevier B.V.