1. Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway.
- Author
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Palacios-Ramírez R, Hernanz R, Martín A, Pérez-Girón JV, Barrús MT, González-Carnicero Z, Aguado A, Jaisser F, Briones AM, Salaices M, and Alonso MJ
- Subjects
- Animals, Hypertension metabolism, Hypertension pathology, Male, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle metabolism, Oxidative Stress drug effects, PPAR gamma metabolism, Rats, Rats, Inbred SHR, Rats, Wistar, Reactive Oxygen Species metabolism, Endothelin-1 metabolism, Hypertension drug therapy, Hypoglycemic Agents pharmacology, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Myocytes, Smooth Muscle drug effects, Pioglitazone pharmacology
- Abstract
Endothelin-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 phenylephrine-induced contraction through ET
A 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.- Published
- 2019
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