title: p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes.
abstract: BACKGROUND
  Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A body of evidence suggests that p-cresyl sulfate (PCS), a uremic toxin, is associated with the cardiovascular mortality rate of patients with chronic kidney disease; however, the molecular mechanisms underlying this feature have not yet been fully elucidated.
  
  
  RESULTS
  We aimed to determine whether PCS accumulation could adversely affect cardiac dysfunction via direct cytotoxicity to cardiomyocytes. In mice that underwent 5/6 nephrectomy, PCS promoted cardiac apoptosis and affected the ratio of left ventricular transmitral early peak flow velocity to left ventricular transmitral late peak flow velocity (the E/A ratio) observed by echocardiography (n=8 in each group). Apocynin, an inhibitor of NADPH oxidase activity, attenuates this alteration of the E/A ratio (n=6 in each group). PCS also exhibited proapoptotic properties in H9c2 cells by upregulating the expression of p22(phox) and p47(phox), NADPH oxidase subunits, and the production of reactive oxygen species. Apocynin and N-acetylcysteine were both able to suppress the effect of PCS, underscoring the importance of NADPH oxidase activation for the mechanism of action.
  
  
  CONCLUSIONS
  This study demonstrated that the cardiac toxicity of PCS is at least partially attributed to induced NADPH oxidase activity and reactive oxygen species production facilitating cardiac apoptosis and resulting in diastolic dysfunction.
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.) Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., Y.D., Y.C., L.L., R.Z.).
authors.forename: Hui
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.).
authors.forename: Jinzhou
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.).
authors.forename: Zhengbin
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.).
authors.forename: Jingwei
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.).
authors.forename: Run
authors.initials: R
authors.lastname: Du
authors.affiliation: Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., Y.D., Y.C., L.L., R.Z.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., Y.D., Y.C., L.L., R.Z.).
authors.forename: Yanjia
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.).
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.) Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., Y.D., Y.C., L.L., R.Z.).
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., J.Z., Z.Z., J.N., R.D., Z.W., L.L., R.Z.) Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.H., Y.D., Y.C., L.L., R.Z.).
authors.forename: Ruiyan
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000000981:diagnostic imaging / Q000209:etiology*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003408:Cresols / Q000378:metabolism*; D004452:Echocardiography; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D013463:Sulfuric Acid Esters / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D000098:Acetophenones; D003408:Cresols; D017382:Reactive Oxygen Species; D013463:Sulfuric Acid Esters; C408690:4-cresol sulfate; C056165:acetovanillone; D053148:Caspase 3
keywords: apoptosis; cardiac dysfunction; chronic kidney disease; nicotinamide adenine dinucleotide phosphate oxidase; p‐cresyl sulfate