Up-regulation of contractile endothelin receptors by airborne fine particulate matter in rat mesenteric arteries via activation of MAPK pathway

摘要

Fine particle matters (PM~(2.5)) is a well-known risk factor for cardiovascular diseases. However, the underlying molecular mechanisms are largely unknown. Vascular hyper-reactivity plays an important roles in the pathogenesis of cardiovascular diseases. The present study was designed to investigate a hypothesis that PM~(2.5)up-regulated endothelin receptors in mesenteric artery and the potential underlying mechanisms. Rat mesenteric arteries were cultured with PM~(2.5). The artery contractile responses were recorded by a sensitive myograph. ET~(B)and ET~(A)receptor expressions of mRNA and protein were assessed by quantitative real-time PCR, Western blotting, and immunohistochemistry, respectively. Results showed that ET~(B)receptor agonist, sarafotoxin 6c induced a negligible contraction in fresh artery segments, while ET~(A)receptor agonist, ET-1 induced an obvious contraction. After organ culture, the contraction curve mediated by ET~(B)and ET~(A)receptors were shifted toward the left. PM~(2.5)1.0?μg/ml cultured for 16?h further enhanced ET~(B)and ET~(A)receptor-mediated contractile responses with a markedly increased maximal contraction. The organ culture enhanced ET~(B)and ET~(A)receptor mRNA and protein levels from fresh arteries, which were further increased by PM~(2.5). The U0126 (MEK/ERK1/2 inhibitor) and SB203580 (p38 inhibitor) significantly attenuated both organ cultured-induced and PM~(2.5)-induced up-regulation of ET~(B)receptor. U0126 also suppressed organ culture-increased and PM~(2.5)-increased expressions of ET~(A)receptor. SB203580 only suppressed PM~(2.5)-induced enhanced expressions of ET~(A)receptor In conclusion, airborne PM~(2.5)up-regulates ET~(B)and ET~(A)receptors of mesenteric artery via p38 MAPK and MEK/ERK1/2 MAPK pathways.