title: Phosphocreatine protects against LPS-induced human umbilical vein endothelial cell apoptosis by regulating mitochondrial oxidative phosphorylation.
abstract: Phosphocreatine (PCr) is an exogenous energy substance, which provides phosphate groups for adenosine triphosphate (ATP) cycle and promotes energy metabolism in cells. However, it is still unclear whether PCr has influenced on mitochondrial energy metabolism as well as oxidative phosphorylation (OXPHO) in previous studies. Therefore, the aim of the present study was to investigate the regulation of PCr on lipopolsaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs) and mitochondrial OXPHO pathway. PCr protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c (Cyt C), Ca(2+), reactive oxygen species and subsequent activation of caspases, and increasing Bcl2 expression, while suppressing Bax expression. More importantly, PCr significantly improved mitochondrial swelling and membrane potential, enhanced the activities of ATP synthase and mitochondrial creatine kinase (CKmt) in creatine shuttle, influenced on respiratory chain enzymes, respiratory control ratio, phosphorus/oxygen ratio and ATP production of OXPHO. Above PCr-mediated mitochondrial events were effectively more favorable to reduced form of flavin adenine dinucleotide (FADH2) pathway than reduced form of nicotinamide-adenine dinucleotid pathway in the mitochondrial respiratory chain. Our results revealed that PCr protects against LPS-induced HUVECs apoptosis, which probably related to stabilization of intracellular energy metabolism, especially for FADH2 pathway in mitochondrial respiratory chain, ATP synthase and CKmt. Our findings suggest that PCr may play a certain role in the treatment of atherosclerosis via protecting endothelial cell function.
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.|Pharmacy Department, Dalian Municipal Central Hospital, Dalian, China.
authors.forename: Zhengwu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Neurology Department, Dalian Municipal Central Hospital, Dalian, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Anil
authors.initials: A
authors.lastname: Ahsan
authors.affiliation: Pharmacy Department, Dalian Municipal Central Hospital, Dalian, China.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Xi
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chu
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Yushu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Public Health Department, Dalian Medical University, Dalian, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Piao
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Han
authors.affiliation: Department of Pharmacology, Dalian Medical University, West Section 9, South Road of Lvshun, Dalian, 116044, China. tangzeyao@aliyun.com.
authors.forename: Zeyao
authors.initials: Z
authors.lastname: Tang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000188:drug therapy; D020169:Caspases / Q000378:metabolism; D052281:Creatine Kinase, Mitochondrial Form / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D008933:Mitochondrial Swelling / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010725:Phosphocreatine / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C000595707:BCL2 protein, human; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D052281:Creatine Kinase, Mitochondrial Form; D020169:Caspases
keywords: Human umbilical vein endothelial cells; Lipopolysaccharide; Mitochondrial apoptosis; Oxidative phosphorylation; Phosphocreatine