ORIGINAL RESEARCH

Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition Yang Liu, MD;* Yu Liu, MD;* Xun Liu, MD;* Jie Chen, MPH;* Kun Zhang, MD; Feifei Huang, MD; Jing-Feng Wang, MD; Wanchun Tang, MD, FAHA; Hui Huang, MD, PhD

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. Methods and 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. ( J Am Heart Assoc. 2015;4:e001598 doi: 10.1161/JAHA.114.001598) Key Words: cardiac remodeling • cardiorenal syndrome • extracellular signal-regulated kinase 1/2 • fibroblast growth factor • pharmacology

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he heart and kidneys have a complicated and bidirectional interrelationship. The impaired function of 1 organ usually has a detrimental effect on the other, which in turn injures the function and structure of both organs. This interrelationship has been defined as cardiorenal syndrome (CRS).1 Type 4 CRS refers to the injury of cardiovascular structure and function in the setting of chronic kidney disease

(CKD) and is also called chronic renocardiac syndrome.1 Previous studies showed that even mild impairment of renal function was associated with significantly elevated morbidity and mortality associated with cardiovascular diseases.2 Cardiovascular diseases, especially heart failure, are the major causes of death in CKD patients.3 The prevalence of CKD worldwide is estimated to be 8% to 16%,4 and the high

From the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China (Yang L., J.C., K.Z., F.H., J.-F.W., W.T., H.H.); Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China (Yang L., Yu 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 (Yu L.); Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (X.L.); Weil Institute of Critical Care Medicine, Rancho Mirage, CA, USA (W.T.). *Dr Yang Liu, Dr Yu Liu, Dr Xun Liu, and Mrs Chen contributed equally to this research study. Correspondence to: Hui Huang, MD, PhD, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, 107 W Yanjiang Rd, Guangzhou 510120, China. E-mail: [email protected] Received November 8, 2014; accepted May 15, 2015. ª 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

DOI: 10.1161/JAHA.114.001598

Journal of the American Heart Association

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Apocynin Attenuates Cardiac Injury in Type 4 CRS

Liu et al

Methods Study Population and Data Collection Patients admitted to Sun Yat-sen Memorial Hospital of Sun Yat-sen University for primary CKD during June to December DOI: 10.1161/JAHA.114.001598

in 2013 were enrolled in this cross-sectional study. Type 4 CRS is defined as cardiac abnormalities such as decreased cardiac function in the setting of primary CKD.1 In this study, patients with both moderate to severe CKD (stage 3 to 5) and heart failure were included in the type 4 CRS group. The patients had previously diagnosed primary CKD. Moderate to serious CKD was diagnosed when the estimated glomerular filtration rate was

Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition.

Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac inju...
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