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.

Expression of the α7 Nicotinic Acetylcholine Receptor Is Critically Required for the Antifibrotic Effect of PHA-543613 on Skin Fibrosis

“…However, silencing the α7nAChR by siRNA abrogated the effect of PHA-543613 in WT MDF. Our findings on the impact of PHA-543613 on TGF-β 1 -mediated signaling are supported by other studies showing that PNU282987, another α7nAChR agonist, ameliorates cardiac remodeling in mice by suppressing TGF-β 1 protein expression and SMAD3 phosphorylation [33]. Moreover, α7nAChR KO MDF disclosed an elevated expression of ECM gene products compared to WT MDF, confirming our in vivo data in α7nAChR KO mice.…”

Diminished α7 nicotinic acetylcholine receptor (α7nAChR) rescues amyloid-β induced atrial remodeling by oxi-CaMKII/MAPK/AP-1 axis-mediated mitochondrial oxidative stress

“…The pseudo activation resulting from Aβ-α7nAChR induced membrane potential change may be another reason of the Ca 2+ kinetics imbalance. Taken together with our findings, the effect of Ca 2+ load might explain the pleiotropic roles of α7nAChR in diverse cell types and the poor uniformity of results of α7nAChR on cardiac function by pharmacological systemic administration in different studies [ 43 , 49 ]. Therefore, in terms of AD therapeutic drugs targeting activating α7nAChR, its side effects on cardiac function need to be paid full attention.…”

Exogenous Hydrogen Sulfide Supplement Attenuates Isoproterenol‐Induced Myocardial Hypertrophy in a Sirtuin 3‐Dependent Manner

“…Male C57BL/6, 129S1/SvImJ (WT), and SIRT3 knockout (KO) mice at 10 weeks of age were randomly administrated with NaHS (50 μ mol/kg/d; Sigma-Aldrich, St. Louis, MO, USA) or normal saline (NS) once daily. After 2 weeks, the mice were given isoproterenol (ISO, 60 mg/kg; Sigma-Aldrich, St. Louis, MO, USA) by intraperitoneal injection to induce myocardial hypertrophy followed by NaHS or NS administration once daily for another 2 weeks [43].…”