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PLCγ1-PKCε-IP
- Source :
- American journal of physiology. Lung cellular and molecular physiology. 314(5)
- Publication Year :
- 2018
-
Abstract
- 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-γ1 (PLCγ1) 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 PLCγ1-dependent inositol 1,4,5-trisphosphate (IP(3)) generation. Exogenous ROS, hydrogen peroxide (H(2)O(2)), increases PLCγ1 phosphorylation at tyrosine-783 and IP(3) production. IP(3) receptor-1 (IP(3)R1) knock-down remarkably diminishes hypoxia- or H(2)O(2)-induced increase in [Ca(2+)](i). Hypoxia or H(2)O(2) increases the activity of IP(3)Rs, which is significantly reduced in protein kinase C-ε (PKCε) knockout PASMCs. A higher PLCγ1 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 H(2)O(2)- 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 PLCγ1 activation, IP(3) production, PKCε activation, IP(3)R1 opening, Ca(2+) release, and contraction in mouse PASMCs; CH enhances PASM PLCγ1 expression, activity, and function, playing an essential role in pulmonary hypertension in mice.
- Subjects :
- Mice, Inbred BALB C
Phospholipase C gamma
Hypertension, Pulmonary
Protein Kinase C-epsilon
Pulmonary Artery
Muscle, Smooth, Vascular
Mitochondria
Mice, Inbred C57BL
Mice
Vasoconstriction
Animals
Inositol 1,4,5-Trisphosphate Receptors
Calcium
Hypoxia
Reactive Oxygen Species
Cells, Cultured
Muscle Contraction
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 15221504
- Volume :
- 314
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Accession number :
- edsair.pmid..........46d189adc512fdb918d78ddac12f123c