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

Roberto Palacios-Ramírez,Zoe González-Carnicero,José V Pérez-Girón,Angela Martín,Andrea Aguado,Ana M Briones,Mercedes Salaices,Raquel Hernanz,María J Alonso,María T Barrús,Frederic Jaisser

doi:10.1038/s41598-019-52839-6

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 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.

Highlights

Endothelin-1 (ET-1), the most important isoform of the endothelin family, is mainly produced by endothelial cells, other vascular cells, including vascular smooth muscle cells (VSMC), release ET-1 in response to different stimuli[11,12]
In vessels or VSMC from hypertensive rats we have analysed: (1) the effect of a subthreshold concentration of ET-1 on phenylephrine responses as well as the role of nitric oxide (NO) and COX-2-derived prostanoids in such effect; (2) the mechanisms involved in the ET-1-induced COX-2 expression; (3) the interference induced by the Peroxisome-proliferator activated receptors-γ (PPARγ) agonist pioglitazone of these ET-1 effects
Our results suggest that reduction of NO bioavailability and increased COX-2-derived PGI2 production, both mediated by oxidative stress, contribute to the hypercontractility to phenylephrine induced by ET-1 acting on ET-1 receptor A (ETA) in vessels from hypertensive animals (Fig. 10)

Summary

Introduction

Endothelin-1 (ET-1), the most important isoform of the endothelin family, is mainly produced by endothelial cells, other vascular cells, including VSMC, release ET-1 in response to different stimuli[11,12]. PPARγ activation reduces ET-1 levels[31,32]; in this sense, we have described that, by downregulating ET-1 transcription, pioglitazone inhibits angiotensin II-associated vascular COX-2 expression in hypertension[5]. We hypothesize that glitazones contribute to reduce the hypertension-associated vascular damage by interfering with ET-1-induced vasoactive and proinflammatory effects. In vessels or VSMC from hypertensive rats we have analysed: (1) the effect of a subthreshold concentration of ET-1 on phenylephrine responses as well as the role of NO and COX-2-derived prostanoids in such effect; (2) the mechanisms involved in the ET-1-induced COX-2 expression; (3) the interference induced by the PPARγ agonist pioglitazone of these ET-1 effects

Methods

Results

Discussion

Conclusion