Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway

Palacios-Ramírez, RobertoHernanz, RaquelMartín, ÁngelaPérez-Girón, VicenteBarrús, María TGonzález-Carnicero, ZoeAguado, AndreaJaisser, FredericBriones, Ana MSalaices, MAlonso, MJ2024-06-042024-06-042019-11-11Palacios-Ramírez, R., Hernanz, R., Martín, A. et al. Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway. Sci Rep 9, 16461 (2019). https://doi.org/10.1038/s41598-019-52839-62045-2322 (online)https://hdl.handle.net/10115/33338Endothelin-1 (ET-1) is an important modulator of the vascular tone and a proinflammatory molecule that contributes to the vascular damage observed in hypertension. Peroxisome-proliferator activated receptors-γ (PPARγ) agonists show cardioprotective properties by decreasing inflammatory molecules such as COX-2 and reactive oxygen species (ROS), among others. We investigated the possible modulatory effect of PPARγ activation on the vascular effects of ET-1 in hypertension. In spontaneously hypertensive rats (SHR), but not in normotensive rats, ET-1 enhanced phenylephrineinduced contraction through ETA by a mechanism dependent on activation of TP receptors by COX-2- derived prostacyclin and reduction in NO bioavailability due to enhanced ROS production. In SHR, the PPARγ agonist pioglitazone (2.5 mg/Kg·day, 28 days) reduced the increased ETA levels and increased those of ETB. After pioglitazone treatment of SHR, ET-1 through ETB decreased ROS levels that resulted in increased NO bioavailability and diminished phenylephrine contraction. In vascular smooth muscle cells from SHR, ET-1 increased ROS production through AP-1 and NFκB activation, leading to enhanced COX-2 expression. These effects were blocked by pioglitazone. In summary, in hypertension, pioglitazone shifts the vascular ETA/ETB ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contraction.engAttribution 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/Peroxisome-proliferator activated receptors-γ (PPARγ) agonists;COX-2;reactive oxygen species; hypertension; resistance arteries; hypertensive rats (SHR).Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathwayinfo:eu-repo/semantics/article10.1038/s41598-019-52839-6info:eu-repo/semantics/openAccess