In vivo PPARα activation attenuates cerebrovascular endothelial dysfunction via impeding NADPH oxidase-derived superoxide and augmenting tetrahydrobiopterin in mineralocorticoid hypertension

Introduction

Hypertension is an independent risk factor for stroke. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptor-dependent transcription factors. PPARα agonist fenofibrate has been shown to abrogate increased arterial prepro-endothelin-1 (preproET-1) and superoxide levels in deoxycorticosterone acetate (DOCA)-salt hypertension with unknown mechanism(s). We have reported that ET-1 induces endothelial dysfunction in the carotid arteries via NADPH oxidase-derived superoxide in this low renin hypertension model. Therefore, the present study tested the hypothesis that chronic PPARα activation in vivo reduces blood pressure and endothelial dysfunction via impeding cerebrovascular NADPH oxidase/superoxide and augmenting eNOS cofactor tetrahydrobiopterin (BH4) in DOCA-salt rats.

Methods

DOCA-salt or sham-operated adult male rats were treated with fenofibrate (150 mg/kg/day) for 4 weeks beginning with DOCA-salt regimen. Oxidative stress markers and endothelial function were determined in the carotid arteries afterwards.

Results

Average systolic blood pressure was significantly increased in DOCA-salt rats (186±8 vs. 122±3 mmHg, DOCA vs. sham), which was blunted by fenofibrate (186±8 vs. 139±6 mmHg, DOCA vs. DOCA+PPARα, all n=11–16, p<0.01). Concomitantly, treatment with fenofibrate significantly reduced arterial NADPH oxidase activity (44.2±4.2 vs. 21.6±1.7 nmol/min/mg tissue DOCA vs. DOCA+PPARα), superoxide level (0.62±0.04 vs. 0.37±0.04 nmol/min/mg protein), VCAM-1 expression (0.46±0.07 vs. 0.28±0.04, VCAM−1/actin ratio, all n=5–10, p<0.05) and serum lipid peroxidation (TBAR 1.92±0.08 vs. 5.18±1.9 mol/L, n=10, p<0.01). Furthermore, treatment with fenofibrate significantly augmented arterial BH4 level (1.23±0.21 vs. 3.21±0.88 pmol/mg protein, n=7–8, p<0.05) and endogenous eNOS activity (6.00±0.40 vs. 12.96±1.61 nmol/mg protein, DOCA vs. DOCA+PPARα, n=8-9, p<0.05), resulting in improved endothelium-dependent NO-mediated relaxation in response to acetylcholine (39.73±2.98 vs. 78.31±3.83%, DOCA vs. DOCA+PPARα, n=9–10, p<0.05).

Conclusion

These findings indicate that in vivo PPARá activation prevents progression of hypertension and reduces cerebrovascular endothelial dysfunction via impeding arterial NADPH oxidase-derived superoxide and augmenting eNOS essential cofactor BH4 in low renin mineralocorticoid hypertension.