American Journal of Physiology - Heart and Circulatory Physiology
American Journal of Physiology - Heart and Circulatory Physiology
5 years ago

PPARα agonists acutely inhibit calcium-independent PLA2 to reduce H2O2-induced contractions in aortae of spontaneously hypertensive rats.

Susan W S Leung, Hui Chen, Ricky Y K Man
Hypertension is associated with endothelial dysfunction, which favors the release of endothelium-derived contracting factors, including vasoconstrictor prostanoids and reactive oxygen species. Peroxisome proliferator-activated receptor α (PPARα) agonists, clinically used as lipid lowering drugs, possess antioxidant properties and exert beneficial effects in the vascular system. The present study aimed to identify the mechanism(s) underlying the acute effects of the PPARα agonists, Wy14643 and fenofibate, on endothelium-dependent contractions, in particular, those related to oxidative stress, in the aorta of the spontaneously hypertensive rat (SHR). Aortic rings, with and without endothelium, of male SHR and normotensive Wistar-Kyoto rats, were suspended in organ chambers for isometric tension measurement and homogenized for enzyme activity assays. Contractions to acetylcholine in quiescent SHR aortae with endothelium were reduced by tiron (superoxide anion scavenger), DETCA (superoxide dismutase inhibitor), and acute treatment to either Wy14643 or fenofibrate. Similarly to contractions evoked by acetylcholine, H2O2-induced increases in tension in SHR aortae involved, in succession, phospholipase A2 (PLA2), cyclooxygenase and thromboxane-prostanoid receptors. Wy14643 or fenofibrate, by decreasing the activity of endothelial calcium-independent PLA2, attenuated the contractions to H2O2 In conclusion, the increased oxidative stress in SHR aorta [mainly increased production of H2O2 and its partially reduced product, hydroxyl radical] contributed to acetylcholine-induced, endothelium-dependent contractions; PPARα agonists likely inhibit the H2O2-mediated contractions by inhibiting endothelial calcium-independent PLA2 The present study highlights the prospective therapeutic effects of PPARα agonists in improving endothelial function in hypertension and other vascular implications due to oxidative stress.

Publisher URL: http://doi.org/10.1152/ajpheart.00314.2017

DOI: 10.1152/ajpheart.00314.2017

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