Aucubin protects against pressure overload-induced cardiac remodelling via the β 3 -adrenoceptor-neuronal NOS cascades

• Published in: British journal of pharmacology Vol. 175; no. 9; pp. 1548 - 1566
• Main Authors: Wu, Qing-Qing, Xiao, Yang, Duan, Ming-Xia, Yuan, Yuan, Jiang, Xiao-Han, Yang, Zheng, Liao, Hai-Han, Deng, Wei, Tang, Qi-Zhu
• Format: Journal Article
• Language: English
• Published: England 01.05.2018
• Subjects: Adrenergic beta-3 Receptor Agonists - pharmacology; Adrenergic beta-3 Receptor Antagonists - pharmacology; Animals; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Cells, Cultured; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Drug Interactions; Heart Failure - prevention & control; Hypertrophy - drug therapy; Hypertrophy - pathology; Iridoid Glucosides - pharmacology; Iridoid Glucosides - therapeutic use; Male; Mice; Mice, Knockout; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nitric Oxide Synthase Type I - biosynthesis; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Oxidative Stress - drug effects; Phenylephrine - pharmacology; Protective Agents - pharmacology; Rats; Receptors, Adrenergic, beta-3 - genetics; Receptors, Adrenergic, beta-3 - metabolism; Ventricular Remodeling - drug effects
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14164

Aucubin, the predominant component of Eucommia ulmoides Oliv., has been shown to have profound effects on oxidative stress. As oxidative stress has previously been demonstrated to contribute to acute and chronic myocardial injury, we tested the effects of aucubin on cardiac remodelling and heart failure. Initially, H9c2 cardiomyocytes and neonatal rat cardiomyocytes pretreated with aucubin (1, 3, 10, 25 and 50 μM) were challenged with phenylephrine. Secondly, the transverse aorta was constricted in C57/B6 and neuronal NOS (nNOS)-knockout mice, then aucubin (1 or 5 mg·kg body weight day ) was injected i.p. for 25 days. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers. Oxidative stress was evaluated by examining ROS generation, oxidase activity and NO generation. NOS expression was determined by Western blotting. Aucubin effectively suppressed cardiac remodelling; in mice, aucubin substantially inhibited pressure overload-induced cardiac hypertrophy, fibrosis and inflammation, whereas knocking out nNOS abolished these cardioprotective effects of aucubin. Blocking or knocking down the β -adrenoceptor abolished the protective effects of aucubin in vitro. Furthermore, aucubin enhanced the protective effects of a β -adrenoceptor agonist in vitro by increasing cellular cAMP levels, whereas treatment with an adenylate cyclase (AC) inhibitor abolished the cardioprotective effects of aucubin. Aucubin suppresses oxidative stress during cardiac remodelling by increasing the expression of nNOS in a process that requires activation of the β -adrenoceptor/AC/cAMP pathway. These findings suggest that aucubin could have potential as a treatment for cardiac remodelling and heart failure.