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Pioglitazone Modulates the Vascular Contractility in Hypertension by Interference with ET-1 Pathway.
- Source :
-
Scientific reports [Sci Rep] 2019 Nov 11; Vol. 9 (1), pp. 16461. Date of Electronic Publication: 2019 Nov 11. - Publication Year :
- 2019
-
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 <subscript>A</subscript> 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 ET <subscript>A</subscript> levels and increased those of ET <subscript>B</subscript> . After pioglitazone treatment of SHR, ET-1 through ET <subscript>B</subscript> 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 ET <subscript>A</subscript> /ET <subscript>B</subscript> ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contraction.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 31712626
- Full Text :
- https://doi.org/10.1038/s41598-019-52839-6