title: High density lipoprotein from patients with valvular heart disease uncouples endothelial nitric oxide synthase.
abstract: Normal high density lipoprotein (HDL) protects vascular function; however these protective effects of HDL may absent in valvular heart disease (VHD). Because vascular function plays an important role in maintaining the circulation post-cardiac surgery and some patients are difficult to stabilize, we hypothesized that a deleterious vascular effect of HDL may contribute to vascular dysfunction in VHD patients following surgery. HDL was isolated from age-match 28 healthy subjects and 84 patients with VHD and during cardiac surgery. HDL pro-inflammation index was measured and the effects of HDL on vasodilation, protein interaction, generation of nitric oxide (NO) and superoxide were determined. Patients with VHD received either simvastatin (20mg/d) or routine medications, and endothelial effects of HDL were characterized. HDL inflammation index significantly increased in VHD patients and post-cardiac surgery. HDL from VHD patients and post-cardiac surgery significantly impaired endothelium-dependent vasodilation, inhibited both Akt and endothelial nitric oxide synthase (eNOS) phosphorylation at S1177, eNOS associated with heat shock protein 90 (HSP90), NO production and increased eNOS phosphorylation at T495 and superoxide generation. Simvastatin therapy partially reduced HDL inflammation index, improved the capacity of HDL to stimulate eNOS and Akt phosphorylation at S1177, eNOS associated with HSP90, NO production, reduced eNOS phosphorylation at T495 and superoxide generation, and improved endothelium-dependent vasodilation. Our data demonstrated that HDL from VHD patients and cardiac surgery contributed to endothelial dysfunction through uncoupling of eNOS. This deleterious effect can be reversed by simvastatin, which improves the vasoprotective effects of HDL. Targeting HDL may be a therapeutic strategy for maintaining vascular function and improving the outcomes post-cardiac surgery.
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China.
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Chang
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Yuan
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China; Division of Hypertension and Vascular Diseases, PR China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Ou
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China.
authors.forename: Ze-Bang
authors.initials: ZB
authors.lastname: Lin
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Wang
authors.affiliation: Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China; Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
authors.forename: Shen-Ming
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Ying-Qi
authors.initials: YQ
authors.lastname: Xu
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Cui-Ping
authors.initials: CP
authors.lastname: Wang
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, USA; Department of Pharmacology, Rush Medical College, Rush University, Chicago, IL 60612, USA.
authors.forename: Chun-Xiang
authors.initials: CX
authors.lastname: Zhang
authors.affiliation: Division of Cardiac Surgery, PR China; The Key Laboratory of Assisted Circulation, Ministry of Health, PR China; Guangdong Province Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, PR China. Electronic address: oujs@mail.sysu.edu.cn.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Ou
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006349:Heart Valve Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006351:Heart Valves / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019821:Simvastatin / Q000627:therapeutic use; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D018841:HSP90 Heat-Shock Proteins; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D013481:Superoxides; D009569:Nitric Oxide; D019821:Simvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt
keywords: Cardiac surgery; Endothelial nitric oxide synthase; High density lipoprotein; Valve; Vasodilation