title: Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition.
abstract: BACKGROUND
  Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4 CRS, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4 CRS, and explore potential mechanisms.
  
  
  RESULTS
  A cross-sectional study was conducted among patients with type 4 CRS (n=17) and controls (n=16). Compared with controls, patients with type 4 CRS showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague-Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4 CRS, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham-operated animals. Cardiac malondialdehyde, NADPH oxidase activity, fibroblast growth factor-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin II-induced NADPH oxidase-dependent oxidative stress, upregulation of fibroblast growth factor-2 and fibrosis biomarkers, and ERK1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor-2 and fibrosis biomarkers in angiotensin II-treated fibroblasts.
  
  
  CONCLUSIONS
  Oxidative stress is a candidate mediator for type 4 CRS. Apocynin attenuated cardiac injury in type 4 CRS rats via inhibiting NADPH oxidase-dependent oxidative stress-activated ERK1/2 pathway and subsequent fibroblast growth factor-2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS.
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.) Department of Cardiology, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China (Y.L.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (X.L.).
authors.forename: Xun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Feifei
authors.initials: F
authors.lastname: Huang
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Wang
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Weil Institute of Critical Care Medicine, Rancho Mirage, CA (W.T.).
authors.forename: Wanchun
authors.initials: W
authors.lastname: Tang
authors.affiliation: Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Y.L., J.C., K.Z., F.H., J.F.W., W.T., H.H.) Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Y.L., Y.L., J.C., K.Z., F.H., J.F.W., H.H.).
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D059347:Cardio-Renal Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D016022:Case-Control Studies; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D049690:History, Ancient; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; C056165:acetovanillone; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: cardiac remodeling; cardiorenal syndrome; extracellular signal‐regulated kinase 1/2; fibroblast growth factor; pharmacology