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-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.

• Authors: Roberto Palacios-Ramírez, Raquel Hernanz, Angela Martín, José V Pérez-Girón, María T Barrús, Zoe González-Carnicero, Andrea Aguado, Frederic Jaisser, Ana M Briones, Mercedes Salaices, María J Alonso
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 16461 (11 11 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31712626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Hypoglycemic Agents
• PPAR gamma
• Reactive Oxygen Species
• Pioglitazone

Topics

• Animals
• Endothelin-1 (metabolism)
• Hypertension (drug therapy, metabolism, pathology)
• Hypoglycemic Agents (pharmacology)
• Male
• Muscle Contraction (drug effects)
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Myocytes, Smooth Muscle (cytology, drug effects, metabolism)
• Oxidative Stress (drug effects)
• PPAR gamma (metabolism)
• Pioglitazone (pharmacology)
• Rats
• Rats, Inbred SHR
• Rats, Wistar
• Reactive Oxygen Species (metabolism)