Open AccessApocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor‐2 With Oxidative Stress Inhibition
Author(s) -
Liu Yang,
Liu Yu,
Liu Xun,
Chen Jie,
Zhang Kun,
Huang Feifei,
Wang JingFeng,
Tang Wanchun,
Huang Hui
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.114.001598
Subject(s) - apocynin , medicine , nadph oxidase , oxidative stress , angiotensin ii , endocrinology , cardiac fibrosis , fibrosis , cardiorenal syndrome , acute kidney injury , kidney disease , blood pressure
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 ERK 1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK 1/2 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 ERK 1/2 pathway and subsequent fibroblast growth factor‐2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS .