Hydrogen peroxide (H2O2) is an important reactive oxygen species implicated in lung vascular constriction and injury. The purpose of this study was to investigate the role of tyrosine kinases in H2O2-induced vascular contraction and dysfunction. In our study, H2O2 (200 microM) caused an initial transient contraction followed by a strong, sustained contraction in isolated rat pulmonary arteries. Genistein, a tyrosine kinase inhibitor, attenuated both the initial and the sustained contractions. Aminogenistein and tyrphostin 51, specific inhibitors of tyrosine kinases, had the same effects as genistein. Exposure of pulmonary arteries to H2O2 for 1 h caused a significant reduction in the contractile response to KCl or phenylephrine and in the vasodilatory response to acetylcholine (smooth muscle dysfunction). Although tyrosine kinase inhibitors significantly blocked contractions induced by H2O2, pretreatment of pulmonary arteries with these inhibitors before H2O2 exposure did not prevent the decreases in responses to KCl, phenylephrine, or acetylcholine. Removal of extracellular Ca2+ and depletion of intracellular Ca2+ pools by ryanodine or thapsigargin did not inhibit the initial and sustained contractions in response to H2O2. W-7, a calmodulin antagonist, or ML-9, a myosin light chain kinase inhibitor, significantly inhibited the sustained contractions but did not prevent smooth muscle dysfunction induced by H2O2. These data show that 1) exposure to H2O2 causes smooth muscle contractions and dysfunction in isolated pulmonary arteries and 2) activation of tyrosine kinases mediates H2O2-induced contractions; however, tyrosine kinases do not appear to be involved in H2O2-induced inhibition of arterial responses to vasoactive substances. These data suggest that different signaling pathways and mechanisms are involved in H2O2-induced smooth muscle contraction and dysfunction.
An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
