Role of PAR2 in Type 2 Diabetes‐induced Endothelial Dysfunction

Abstract

Previously we have found a critical role of tumor necrosis factor‐α (TNF) in endothelial dysfunction resulting from type 2 diabetes. Because TNF can influence many pathways of inducing oxidative stress and cell injury, our goal was to identify one of the contributing mechanisms. Protease‐activated receptors (PARs), particularly endothelial PAR2 are thought to play a role in inflammatory cardiovasculardisease. We investigated the role of PAR2 in regulating TNF‐induced endothelial dysfunction in Type 2 diabetes. Coronary arterioles of WT (normal) and db/db (diabetic) mice (12–16 weeks) were isolated and pressurized (60 cmH2O). Although vasodilation to endothelium‐independent vasodilator sodium nitroprusside was not different among WT, db/db and dbTNF‐/dbTNF‐ (db/db null for TNF) mice, dilation to endothelium‐dependent agonist ACh was impaired in db/db mice but was greater in dbTNF‐/dbTNF‐compared to db/db (P<0.05). Administration of PAR2 antagonist (FSLLRY‐NH2) partially enhanced ACh‐induced vasodilation in db/db mice. Flow‐induced vasodilation showed similar response to ACh‐induced vasodilation. Both mRNA and protein expression of PAR2 were higher in db/db heart compared to WT heart whereas mRNA and protein expression were reduced in dbTNF‐/dbTNF‐ vs db/db. These results indicate that PAR2 plays a pivotal role in type 2 diabetes‐induced endothelial dysfunction through TNF mechanism.