Abstract
Background/Aims: The effects of oxidative stress on the vascular responsiveness to the agonists of proteinase-activated receptors (PARs) were investigated. Methods: Serum-free incubation was utilized to impose oxidative stress to isolated rat aortas. Spontaneously hypertensive rats (SHR) were investigated as a model of in vivo oxidative stress. Results: Thrombin, trypsin, PAR<sub>1</sub>-activating peptide (PAR<sub>1</sub>-AP), PAR<sub>2</sub>-AP and PAR<sub>4</sub>-AP induced little or no effect in the aortas of female Wistar-Kyoto rats (WKY). Serum-free incubation induced endothelium-dependent relaxant responses to PAR<sub>2</sub> agonists, but not PAR<sub>1</sub> or PAR<sub>4</sub> agonists, in a manner sensitive to diphenyleneiodonium or ascorbic acid. In male aortas, trypsin and PAR<sub>2</sub>-AP induced a transient endothelium-dependent relaxation without serum-free incubation. The acetylcholine-induced endothelium-dependent relaxation and the sodium nitroprusside-induced endothelium-independent relaxation remained unchanged. Immunoblot analyses revealed the upregulation of PAR<sub>2</sub> in endothelial cells, which was abolished by either diphenyleneiodonium or ascorbic acid. Aortas of female SHR expressed a higher level of PAR<sub>2</sub> than WKY and responded to trypsin without serum-free incubation. Treatment with ascorbic acid attenuated the trypsin-induced relaxation and the PAR<sub>2</sub> expression in SHR. Conclusion: This study provides the first evidence that oxidative stress upregulates PAR<sub>2</sub> in endothelial cells, thereby enhancing the endothelium-dependent relaxant response to PAR<sub>2</sub> agonists in rat aortas.
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