Tongxinluo protects against pressure overload-induced heart failure in mice involving VEGF/Akt/eNOS pathway activation

• Published in: PloS one 2014-06, Vol.9 (6), p.e98047-e98047
• Main Authors: Wang, Bo, Yang, Qing, Bai, Wen-wu, Xing, Yi-fan, Lu, Xiao-ting, Sun, Yuan-yuan, Zhao, Yu-xia
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 8-Hydroxydeoxyguanosine; Activation; AKT protein; Analysis; Angiogenesis; Animal diseases; Animal models; Animals; Aorta; Biology and Life Sciences; Capillaries - drug effects; Capillaries - pathology; Capillaries - physiopathology; Cardiomegaly - diagnostic imaging; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiomyocytes; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cardiovascular diseases; Chinese medicine; Coronary artery disease; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Echocardiography; Electron microscopy; Fetuses; Fibrosis; Gene expression; Heart; Heart diseases; Heart failure; Heart Failure - diagnostic imaging; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Function Tests; Heme; Heme oxygenase (decyclizing); Herbal medicine; Hypertrophy; Ischemia; Kinases; Male; Malondialdehyde; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Myocardium - pathology; Myocardium - ultrastructure; NAD(P)H oxidase; Nitric oxide; Nitric Oxide Synthase Type III - metabolism; Oxidases; Oxidative stress; Oxidative Stress - drug effects; Pressure; Proto-Oncogene Proteins c-akt - metabolism; Research and Analysis Methods; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Surgery; Traditional Chinese medicine; Transmission electron microscopy; Ultrasonography; Ultrastructure; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Ventricle; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098047

It has been demonstrated that Tongxinluo (TXL), a traditional Chinese medicine compound, improves ischemic heart disease in animal models via vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The present study aimed to investigate whether TXL protects against pressure overload-induced heart failure in mice and explore the possible mechanism of action. Transverse aortic constriction (TAC) surgery was performed in mice to induce heart failure. Cardiac function was evaluated by echocardiography. Myocardial pathology was detected using hematoxylin and eosin or Masson trichrome staining. We investigated cardiomyocyte ultrastructure using transmission electron microscopy. Angiogenesis and oxidative stress levels were determined using CD31 and 8-hydroxydeoxyguanosine immunostaining and malondialdehyde assay, respectively. Fetal gene expression was measured using real-time PCR. Protein expression of VEGF, phosphorylated (p)-VEGF receptor 2 (VEGFR2), p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p-eNOS, heme oxygenase-1 (HO-1), and NADPH oxidase 4 (Nox4) were measured with western blotting. Twelve-week low- and high-dose TXL treatment following TAC improved cardiac systolic and diastolic function and ameliorated left ventricular hypertrophy, fibrosis, and myocardial ultrastructure derangement. Importantly, TXL increased myocardial capillary density significantly and attenuated oxidative stress injury in failing hearts. Moreover, TXL upregulated cardiac nitrite content and the protein expression of VEGF, p-VEGFR2, p-PI3K, p-Akt, p-eNOS, and HO-1, but decreased Nox4 expression in mouse heart following TAC. Our findings indicate that TXL protects against pressure overload-induced heart failure in mice. Activation of the VEGF/Akt/eNOS signaling pathway might be involved in TXL improvement of the failing heart.