title: Increased LDL electronegativity in chronic kidney disease disrupts calcium homeostasis resulting in cardiac dysfunction.
abstract: Chronic kidney disease (CKD), an independent risk factor for cardiovascular disease, is associated with abnormal lipoprotein metabolism. We examined whether electronegative low-density lipoprotein (LDL) is mechanistically linked to cardiac dysfunction in patients with early CKD. We compared echocardiographic parameters between patients with stage 2 CKD (n = 88) and normal controls (n = 89) and found that impaired relaxation was more common in CKD patients. Reduction in estimated glomerular filtration rate was an independent predictor of left ventricular relaxation dysfunction. We then examined cardiac function in a rat model of early CKD induced by unilateral nephrectomy (UNx) by analyzing pressure-volume loop data. The time constant of isovolumic pressure decay was longer and the maximal velocity of pressure fall was slower in UNx rats than in controls. When we investigated the mechanisms underlying relaxation dysfunction, we found that LDL from CKD patients and UNx rats was more electronegative than LDL from their respective controls and that LDL from UNx rats induced intracellular calcium overload in H9c2 cardiomyocytes in vitro. Furthermore, chronic administration of electronegative LDL, which signals through lectin-like oxidized LDL receptor-1 (LOX-1), induced relaxation dysfunction in wild-type but not LOX-1(-/-) mice. In in vitro and in vivo experiments, impaired cardiac relaxation was associated with increased calcium transient resulting from nitric oxide (NO)-dependent nitrosylation of SERCA2a due to increases in inducible NO synthase expression and endothelial NO synthase uncoupling. In conclusion, LDL becomes more electronegative in early CKD. This change disrupts SERCA2a-regulated calcium homeostasis, which may be the mechanism underlying cardiorenal syndrome.
authors: Division of Cardiology, China Medical University (CMU) Hospital, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, CMU, Taichung, Taiwan.
authors: Kuan-Cheng
authors: KC
authors: Chang
authors: Department of Medicine, Mackay Medical College, New Taipei, Taiwan; L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan.
authors: An-Sheng
authors: AS
authors: Lee
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan.
authors: Wei-Yu
authors: WY
authors: Chen
authors: Division of Cardiology, China Medical University (CMU) Hospital, Taichung, Taiwan.
authors: Yen-Nien
authors: YN
authors: Lin
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan.
authors: Jing-Fang
authors: JF
authors: Hsu
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan; Center for Lipid Biosciences, Kaohsiung Medical University (KMU) Hospital, KMU, Kaohsiung, Taiwan.
authors: Hua-Chen
authors: HC
authors: Chan
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan.
authors: Chia-Ming
authors: CM
authors: Chang
authors: Division of Cardiology, China Medical University (CMU) Hospital, Taichung, Taiwan.
authors: Shih-Sheng
authors: SS
authors: Chang
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan.
authors: Chia-Chi
authors: CC
authors: Pan
authors: Department of Physiology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors: Tatsuya
authors: T
authors: Sawamura
authors: Division of Nephrology, CMU Hospital, Taichung, Taiwan.
authors: Chi-Tzong
authors: CT
authors: Chang
authors: Graduate Institute of Pharmacology, National Taiwan University, Taipei, Taiwan. Electronic address: mingja@ntu.edu.tw.
authors: Ming-Jai
authors: MJ
authors: Su
authors: L5 Research Center, CMU Hospital, CMU, Taichung, Taiwan; Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Center for Lipid and Glycomedicine Research, KMU Hospital, KMU, Kaohsiung, Taiwan. Electronic address: cchen@texasheart.org.
authors: Chu-Huang
authors: CH
authors: Chen
mesh_terms: D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D005355:Fibrosis; D006321:Heart; D006706:Homeostasis; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism; D009392:Nephrectomy; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015538:Nitrosation; D017207:Rats, Sprague-Dawley; D051131:Receptors, Oxidized LDL / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology*; D012084:Renin-Angiotensin System; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D014463:Ultrasonography; D015854:Up-Regulation; D014664:Vasodilation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D051131:Receptors, Oxidized LDL; C099252:oxidized low density lipoprotein; D016875:tau Proteins; D052247:Nitric Oxide Synthase Type II; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: Cardiorenal syndrome; Lipoproteins; SERCA2a; Unilateral nephrectomy