Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol-induced cardiac remodelling in mice through TGF-β1/Smad3 pathway.

Abstract

It is well-accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of α7 nicotinic acetylcholine receptor (α7nAChR) causes an anti-inflammatory effect, the role of α7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific α7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross-sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP-9), transforming growth factor β1 (TGF-β1), and Smad3 were analyzed by Western blot. ISO-induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP-9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF-β1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF-β1/Smad3 pathway. These data imply that the α7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases.

• Authors: Yong-Hua Yang, Huan-Le Fang, Ming Zhao, Xiang-Lan Wei, Ning Zhang, Shun Wang, Yi Lu, Xiao-Jiang Yu, Lei Sun, Xi He, Dong-Ling Li, Jin-Jun Liu, Wei-Jin Zang
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 44 Issue 12 Pg. 1192-1200 (Dec 2017) ISSN: 1440-1681 [Electronic] Australia
• PMID: 28732106 (Publication Type: Journal Article)
• Copyright: © 2017 John Wiley & Sons Australia, Ltd.

Chemical References

• Benzamides
• Bridged Bicyclo Compounds
• Nicotinic Agonists
• PNU-282987
• Smad3 Protein
• Smad3 protein, mouse
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• alpha7 Nicotinic Acetylcholine Receptor
• Isoproterenol

Topics

• Animals
• Benzamides (administration & dosage, therapeutic use)
• Bridged Bicyclo Compounds (administration & dosage, therapeutic use)
• Cardiomegaly (drug therapy, metabolism, pathology)
• Isoproterenol (pharmacology)
• Male
• Mice, Inbred BALB C
• Myocardium (metabolism, pathology)
• Nicotinic Agonists (administration & dosage, therapeutic use)
• Signal Transduction
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Ventricular Remodeling (drug effects)
• alpha7 Nicotinic Acetylcholine Receptor (agonists)