Attenuated PGI2synthesis in obese Zucker rats

Abstract

In obesity, skeletal muscle blood flow during exercise (functional hyperemia) is impaired. We have indirectly demonstrated that an altered arachidonic acid metabolism is responsible for the impaired functional vasodilation in the obese Zucker rat (OZR), a model of obesity. In this study, we tested the hypothesis that there is an impaired release of PGI2due to a nitration of PGI2synthase (PGIS), which is associated with a decreased prostanoid receptor expression. PGI2, PGE2, and thromboxane A2(TXA2) release were determined in vitro using ELISA under basal conditions and in response to arachidonic acid (AA) administration (50 μM). Immunofluorescence of PGI2and TXA2receptors (IP and TP, respectively) was determined in dispersed vascular smooth muscle cells (VSMCs). Nitration of tyrosine residues of the PGIS enzyme was determined using immunoprecipitation and Western blot analysis. Following AA administration, PGI2and PGE2release were attenuated in OZR compared with lean Zucker rats (LZR; controls). Basal and AA-induced TXA2release were not significantly different between groups. IP and TP immunofluorescence were not significantly different between OZR and LZR groups. OZR exhibited elevated nitration of tyrosine residues of PGIS compared with LZR. These results suggest that alterations in the PGI2pathway (attenuated PGI2synthesis), and not the TXA2pathway (normal TXA2synthesis/no change in TP receptor expression), underlie the attenuated functional hyperemia in the OZR.