Nobiletin alleviates vascular alterations through modulation of Nrf-2/HO-1 and MMP pathways in l-NAME induced hypertensive rats

Abstract

Nobiletin, a citrus flavonoid, exhibits a wide range of biological activities. This study investigated the effect of nobiletin on vascular dysfunction and remodeling in L-NAME-induced hypertensive rats. Male Sprague-Dawley rats were given L-NAME (40 mg kg⁻¹) for five weeks to induce hypertension and treated with nobiletin (20 or 40 mg kg⁻¹) or captopril (5 mg kg⁻¹) for the last two weeks. Nobiletin or captopril significantly reduced blood pressure and the enhancement of the contractile response to sympathetic nerve stimulation in the mesenteric vascular beds of L-NAME rats (p < 0.05). Both agents improved the impairment of vasorelaxation responses to acetylcholine in mesenteric vascular beds and aortic rings in L-NAME rats (p < 0.05). Moreover, nobiletin and captopril decreased oxidative stress markers, restored the abnormality of plasma NOx and the protein expressions of eNOS, Nrf-2 and HO-1 observed in L-NAME rats (p < 0.05). Increases in aortic wall thickness, cross sectional area, vascular smooth muscle cells and collagen deposition that occurred in L-NAME rats were reduced by nobiletin or captopril (p < 0.05). These reductions were associated with the suppression of matrix metalloproteinase (MMP)-2 and MMP-9 protein expression (p < 0.05). These findings indicated that nobiletin had antihypertensive effects with amelioration of vascular alterations. The molecular mechanism is likely to involve the restoration of Nrf-2/HO-1/MMP signaling pathways.