ROS-dependent signaling mechanisms for hypoxic Ca(2+) responses in pulmonary artery myocytes.
Hypoxic exposure causes pulmonary vasoconstriction, which serves as a critical physiologic process that ensures regional alveolar ventilation and pulmonary perfusion in the lungs, but may become an essential pathologic factor leading to pulmonary hypertension. Although the molecular mechanisms underlying hypoxic pulmonary vasoconstriction and associated pulmonary hypertension are uncertain, increasing evidence indicates that hypoxia can result in a significant increase in intracellular reactive oxygen species concentration ([ROS](i)) through the mitochondrial electron-transport chain in pulmonary artery smooth muscle cells (PASMCs). The increased mitochondrial ROS subsequently activate protein kinase C-epsilon (PKCepsilon) and NADPH oxidase (Nox), providing positive mechanisms that further increase [ROS](i). ROS may directly cause extracellular Ca(2+) influx by inhibiting voltage-dependent K(+) (K(V)) channels and opening of store-operated Ca(2+) (SOC) channels, as well as intracellular Ca(2+) release by activating ryanodine receptors (RyRs), leading to an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) and associated contraction. In concert with ROS, PKCepsilon may also affect K(V) channels, SOC channels, and RyRs, contributing to hypoxic Ca(2+) and contractile responses in PASMCs.
Wang
Yong-Xiao
YX
Center for Cardiovascular Sciences, Albany Medical College, New York 12208, USA. wangy@mail.amc.edu
Zheng
Yun-Min
YM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004579:Electron Transport / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D007473:Ion Channels; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D051744:Protein Kinase C-epsilon; D002118:Calcium