title: Endothelium-independent hypoxic contraction of porcine coronary arteries may be mediated by activation of phosphoinositide 3-kinase/Akt pathway.
abstract: Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays an essential role in the regulation of vascular tone. The present study aimed to determine its role in hypoxic coronary vasoconstriction. Isometric tension of isolated porcine coronary arteries was measured with organ chamber technique; the protein levels of phosphorylated and total MLC were examined by Western blotting; the activities of PI3K and Rho kinase were determined by the phosphorylation of their respective target protein Akt and MTPT1. Acute hypoxia induced a rapid contraction followed by a short-term relaxation and then a sustained contraction in porcine coronary arteries. The rapid but not the sustained contraction was abolished by endothelium removal. The sustained contraction was attenuated by inhibitors of PI3K (LY294002) and Akt (Akt-I). The attenuation effect caused by LY294002 was not affected by nifedipine, but was abolished by Y27632, an inhibitor of Rho kinase. The sustained hypoxic contraction was associated with altered phosphorylation of MLC and Akt, which was inhibited by LY294002. The sustained hypoxic contraction was also accompanied with increased phosphorylation of MYPT1, which was inhibited by LY294002 and Y27632. This study demonstrates that sustained hypoxia causes porcine coronary artery to contract in an endothelium-independent manner. An increased PI3K/Akt/Rho kinase signaling may be involved.
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Department of Physiology, Heze Medical College, Heze, Shandong, China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Zhengju
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, China. Electronic address: doudou@bjmu.edu.cn.
authors.forename: Dou
authors.initials: D
authors.lastname: Dou
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003331:Coronary Vessels / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology*; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000577:Amides; D002867:Chromones; D009025:Morpholines; D011725:Pyridines; C108830:Y 27632; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases
keywords: Akt1/2 kinase inhibitor (Pubchem CID: 16218954); Contractility; Coronary circulation; Hypoxia; LY294002 (Pubchem CID: 3973); Myosin; Nitro-L-arginine (Pubchem CID: 4367); U46619 (Pubchem CID: 16219283); Vasospasm; Y27632 (Pubchem CID: 9901617)