title: High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery.
abstract: Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91(phox), p47(phox), p67(phox), and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China ; Department of Medicinal Chemistry, School of Pharmacy, Chengdu Medical College, Chengdu 610083, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Chengdu Military General Hospital, Chengdu 610083, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu 610052, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu 610052, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu 610052, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu 610052, China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu 610052, China.
authors.forename: Chengmin
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002315:Cardiopulmonary Bypass; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005976:Glutaral / Q000737:chemistry; D006454:Hemoglobins / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008315:Malondialdehyde / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000209:etiology; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D021122:Protein Subunits / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001802:Blood Substitutes; D006454:Hemoglobins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D052279:Creatine Kinase, MB Form; D005976:Glutaral