Dataset Information

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

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-? (PPAR?) 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 PPAR? 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 PPAR? agonist pioglitazone (2.5?mg/Kg·day, 28 days) reduced the increased ET_A levels and increased those of ET_B. After pioglitazone treatment of SHR, ET-1 through ET_B 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 NF?B activation, leading to enhanced COX-2 expression. These effects were blocked by pioglitazone. In summary, in hypertension, pioglitazone shifts the vascular ET_A/ET_B ratio, reduces ROS/COX-2 activation and increases NO availability; these changes explain the effect of ET-1 decreasing phenylephrine-induced contraction.

SUBMITTER: Palacios-Ramirez R

PROVIDER: S-EPMC6848177 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Palacios-Ramírez Roberto R Hernanz Raquel R Martín Angela A Pérez-Girón José V JV Barrús María T MT González-Carnicero Zoe Z Aguado Andrea A Jaisser Frederic F Briones Ana M AM Salaices Mercedes M Alonso María J MJ

Scientific reports 20191111 1

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 hyperte ...[more]

PMID: 31712626

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Project description:We sought to determine the antiatherosclerotic properties of pioglitazone using multimethod noninvasive imaging techniques.Inflammation is an essential component of vulnerable or high-risk atheromas. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, possesses potent anti-inflammatory properties. We aimed to quantify noninvasively the anti-inflammatory effects of pioglitazone on atheroma using (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI).Atherosclerotic plaques were induced in the aorta of 15 New Zealand white rabbits by a combination of a hyperlipidemic diet and 2 balloon endothelial denudations. Nine rabbits continued the same diet, whereas 6 rabbits received pioglitazone (10 mg/kg orally) in addition to the diet. Twelve animals underwent (18)F-FDG-PET/CT, and 15 animals underwent DCE-MRI at baseline, 1 month, and 3 months after treatment initiation. Concomitantly, serum metabolic parameters were monitored. After imaging was completed, aortic histologic analysis and correlation analysis were performed.The (18)F-FDG-PET/CT imaging detected an increase in average standardized uptake value in the control group (p < 0.01), indicating progressive inflammation, whereas stable standardized uptake values were observed in the treatment group, indicating no progression. The DCE-MRI analysis detected a significant decrease in the area under the curve for the pioglitazone group (p < 0.01). Immunohistologic examination of the aortas demonstrated a significant decrease in macrophage and oxidized phospholipid immunoreactivity in the pioglitazone group (p = 0.04 and p = 0.01, respectively) with respect to control animals, underlining the imaging results. Serum metabolic parameters showed no difference between groups. Strong positive correlations between standardized uptake value and macrophage density and between area under the curve and neovessels were detected (r(2) = 0.86 and p < 0.0001, and r(2) = 0.66 and p = 0.004, respectively).Both (18)F-FDG-PET/CT and DCE-MRI demonstrate noninvasively the anti-inflammatory effects of pioglitazone on atheroma. Both imaging methods seem suited to monitor inflammation in atherosclerosis.

Dataset Information

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

Publications

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

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