Relaxation of human pulmonary arteries by PPARγ agonists

Abstract

It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01–100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the KATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration–response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and KATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.

New horizons in pulmonary arterial hypertension therapies

“…This study found that the PPARc antagonists pioglitazone and rosiglitazone act to relax human pulmonary arteries, and that rosiglitazone was the most potent vasodilator [82]. These results further suggest that PPARc antagonists may also be a novel therapeutic route for the treatment of PAH.…”

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

“…PPARγ activation is reported to increase blood flow via vasodilation [31, 42]. We examined vascular response to PPARγ in HS and NS-fed A 2A AR +/+ and A 2A AR −/− mice using selective PPARγ agonist, Rosiglitazone.…”

“…Thiazolidinedione (TZD), specific PPARγ ligands, has been reported to lower blood pressure and provide cardiovascular benefits through regulating vascular function and vascular tone [30]. Studies have demonstrated that PPARγ activation elicits relaxation in pulmonary arteries by activating K ATP channels through unknown mechanism [31]. …”

Vildagliptin promotes improvement in pulmonary arterial hypertension: incretin-based therapy at a follow-up of 3 years

“…The use of rosiglitazone, a PPARgamma agonist, promoted pulmonary artery vasorelaxation in an in vitro study [12]. Another curious fact is the improvement of obese patients with PAH after undergoing bariatric surgery, which, in addition to inducing significant weight loss, also promotes an increase in incretin secretion, including GLP-1 [9].…”