| First Author | Yadav VR | Year | 2018 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 314 |
| Issue | 5 | Pages | L724-L735 |
| PubMed ID | 29388468 | Mgi Jnum | J:261375 |
| Mgi Id | MGI:6155477 | Doi | 10.1152/ajplung.00243.2017 |
| Citation | Yadav VR, et al. (2018) PLCgamma1-PKCepsilon-IP3R1 signaling plays an important role in hypoxia-induced calcium response in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 314(5):L724-L735 |
| abstractText | Hypoxia-induced pulmonary vasoconstriction (HPV) is attributed to an increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in pulmonary artery smooth muscle cells (PASMCs). We have reported that phospholipase C-gamma1 (PLCgamma1) plays a significant role in the hypoxia-induced increase in [Ca(2+)]i in PASMCs and attendant HPV. In this study, we intended to determine molecular mechanisms for hypoxic Ca(2+) and contractile responses in PASMCs. Our data reveal that hypoxic vasoconstriction occurs in pulmonary arteries, but not in mesenteric arteries. Hypoxia caused a large increase in [Ca(2+)]i in PASMCs, which is diminished by the PLC inhibitor U73122 and not by its inactive analog U73433 . Hypoxia augments PLCgamma1-dependent inositol 1,4,5-trisphosphate (IP3) generation. Exogenous ROS, hydrogen peroxide (H2O2), increases PLCgamma1 phosphorylation at tyrosine-783 and IP3 production. IP3 receptor-1 (IP3R1) knock-down remarkably diminishes hypoxia- or H2O2-induced increase in [Ca(2+)]i. Hypoxia or H2O2 increases the activity of IP3Rs, which is significantly reduced in protein kinase C-epsilon (PKCepsilon) knockout PASMCs. A higher PLCgamma1 expression, activity, and basal [Ca(2+)]i are found in PASMCs, but not in mesenteric artery smooth muscle cells from mice exposed to chronic hypoxia (CH) for 21 days. CH enhances H2O2- and ATP-induced increase in [Ca(2+)]i in PASMCs and PLC-dependent, norepinephrine-evoked pulmonary vasoconstriction. In conclusion, acute hypoxia uniquely causes ROS-dependent PLCgamma1 activation, IP3 production, PKCepsilon activation, IP3R1 opening, Ca(2+) release, and contraction in mouse PASMCs; CH enhances PASM PLCgamma1 expression, activity, and function, playing an essential role in pulmonary hypertension in mice. |
