Molecular mechanisms and cell signaling of 20-hydroxyeicosatetraenoic acid in vascular pathophysiology.
Cytochrome P450s enzymes catalyze the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid and hydroxyeicosatetraeonic acid (HETEs). 20-HETE is a vasoconstrictor that depolarizes vascular smooth muscle cells by blocking K+ channels. EETs serve as endothelial derived hyperpolarizing factors. Inhibition of the formation of 20-HETE impairs the myogenic response and autoregulation of renal and cerebral blood flow. Changes in the formation of EETs and 20-HETE have been reported in hypertension and drugs that target these pathways alter blood pressure in animal models. Sequence variants in CYP4A11 and CYP4F2 that produce 20-HETE, UDP-glucuronosyl transferase involved in the biotransformation of 20-HETE and soluble epoxide hydrolase that inactivates EETs are associated with hypertension in human studies. 20-HETE contributes to the regulation of vascular hypertrophy, restenosis, angiogenesis and inflammation. It also promotes endothelial dysfunction and contributes to cerebral vasospasm and ischemia-reperfusion injury in the brain, kidney and heart. This review will focus on the role of 20-HETE in vascular dysfunction, inflammation, ischemic and hemorrhagic stroke and cardiac and renal ischemia reperfusion injury.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216.
Fan
F
Fan
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216.
Ying
Y
Ge
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216 and Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University, Qingdao, China.
Wenshan
W
Lv
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216.
Matthew R
MR
Elliott
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216 and Department of General Medicine and Rehabilitation, Tohoku Medical and Pharmaceutical University School of Medicine, Sendai, Japan.
Yoshikazu
Y
Muroya
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216 and Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Takashi
T
Hirata
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216.
George W
GW
Booz
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, rroman@umc.edu.
Richard J
RJ
Roman
D000818:Animals; D001808:Blood Vessels / Q000503:physiopathology*; D000070642:Brain Injuries, Traumatic / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D018919:Neovascularization, Physiologic; D010974:Platelet Aggregation / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology; D015398:Signal Transduction; D020521:Stroke / Q000503:physiopathology; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology; D014657:Vasculitis / Q000503:physiopathology
D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid