https://scholars.lib.ntu.edu.tw/handle/123456789/563934
標題: | Increased LDL electronegativity in chronic kidney disease disrupts calcium homeostasis resulting in cardiac dysfunction | 作者: | Chang K.-C. Lee A.-S. Chen W.-Y. Lin Y.-N. Hsu J.-F. Chan H.-C. Chang C.-M. Chang S.-S. Pan C.-C. Sawamura T. Chang C.-T. MING-JAI SU Chen C.-H. |
關鍵字: | Cardiorenal syndrome; Lipoproteins; SERCA2a; Unilateral nephrectomy | 公開日期: | 2015 | 卷: | 84 | 起(迄)頁: | 36-44 | 來源出版物: | Journal of Molecular and Cellular Cardiology | 摘要: | 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. ? 2015 Elsevier Ltd. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/563934 | ISSN: | 222828 | DOI: | 10.1016/j.yjmcc.2015.03.016 | SDG/關鍵字: | low density lipoprotein; nitric oxide synthase; oxidized low density lipoprotein receptor 1; calcium; inducible nitric oxide synthase; low density lipoprotein; oxidized low density lipoprotein; oxidized low density lipoprotein receptor; sarcoplasmic reticulum calcium transporting adenosine triphosphatase; tau protein; adult; animal cell; animal experiment; animal model; animal tissue; Article; calcium cell level; calcium homeostasis; chronic kidney disease; controlled study; disease association; echocardiography; enzyme phosphorylation; functional assessment; heart disease; heart function; heart muscle cell; in vitro study; in vivo study; male; molecular dynamics; nonhuman; priority journal; protein determination; protein expression; protein function; rat; syndrome delineation; animal; biological model; C57BL mouse; case control study; chronic kidney failure; demography; echography; female; fibrosis; heart; homeostasis; human; metabolism; nephrectomy; nitrosation; pathophysiology; renin angiotensin aldosterone system; Sprague Dawley rat; upregulation; vasodilatation; Mus; Rattus; Adult; Animals; Calcium; Case-Control Studies; Demography; Female; Fibrosis; Heart; Homeostasis; Humans; Lipoproteins, LDL; Male; Mice, Inbred C57BL; Models, Biological; Myocytes, Cardiac; Nephrectomy; Nitric Oxide Synthase Type II; Nitrosation; Rats, Sprague-Dawley; Receptors, Oxidized LDL; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sarcoplasmic Reticulum Calcium-Transporting ATPases; tau Proteins; Up-Regulation; Vasodilation |
顯示於: | 藥理學科所 |
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