PLCγ1-PKCε-IP3R1 signaling plays an important role in hypoxia-induced calcium response in pulmonary artery smooth muscle cells

被引:32
|
作者
Yadav, Vishal R. [1 ]
Song, Tengyao [1 ]
Mei, Lin [1 ]
Joseph, Leroy [1 ]
Zheng, Yun-Min [1 ]
Wang, Yong-Xiao [1 ]
机构
[1] Albany Med Coll, Dept Mol & Cellular Physiol, 47 New Scotland Ave, Albany, NY 12208 USA
基金
美国国家卫生研究院;
关键词
calcium; hypoxia; hypoxia-induced pulmonary vasoconstriction; inositol 1,4,5-trisphosphate receptor-1; phospholipase C-gamma 1; protein kinase C-epsilon; reactive oxygen species; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; INDUCED CA2+ SENSITIZATION; PHOSPHOLIPASE-C-GAMMA; PROTEIN-KINASE-C; RYANODINE RECEPTORS; INTRACELLULAR CALCIUM; HYDROGEN-PEROXIDE; MESENTERIC-ARTERY; UP-REGULATION; VASOCONSTRICTION;
D O I
10.1152/ajplung.00243.2017
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Hypoxia-induced pulmonary vasoconstriction (HPV) is attributed to an increase in intracellular Ca2+ concentration ([Ca2+](i)) in pulmonary artery smooth muscle cells (PASMCs). We have reported that phospholipase C-gamma 1 (PLC gamma 1) plays a significant role in the hypoxiainduced increase in [Ca2+](i) in PASMCs and attendant HPV. In this study, we intended to determine molecular mechanisms for hypoxic Ca2+ 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 [Ca2+](i) in PASMCs, which is diminished by the PLC inhibitor U73122 and not by its inactive analog U73433. Hypoxia augments PLC gamma 1-dependent inositol 1,4,5-trisphosphate (IP3) generation. Exogenous ROS, hydrogen peroxide (H2O2), increases PLC gamma 1 phosphorylation at tyrosine783 and IP3 production. IP3 receptor-1 (IP3R1) knock-down remarkably diminishes hypoxia-or H2O2-induced increase in [Ca2+](i). Hypoxia or H2O2 increases the activity of IP(3)Rs, which is significantly reduced in protein kinase C-epsilon (PKC epsilon) knockout PASMCs. A higher PLC gamma 1 expression, activity, and basal [Ca2+](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 [Ca2+](i)in PASMCs and PLC-dependent, norepinephrine-evoked pulmonary vasoconstriction. In conclusion, acute hypoxia uniquely causes ROS-dependent PLC gamma 1 activation, IP3 production, PKCe activation, IP(3)R1 opening, Ca2+ release, and contraction in mouse PASMCs; CH enhances PASM PLC gamma 1 expression, activity, and function, playing an essential role in pulmonary hypertension in mice.
引用
收藏
页码:L724 / L735
页数:12
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