Modulation of inflammatory responses in heart failure via activation of alpha-7 nicotinic acetylcholine receptor agonist GTS-21

Abstract

Abstract Heart failure (HF) is a prominent health concern amongst the public with prevalence rate being over 5.8 million in the USA. Inflammation and cytokine signaling are two main factors that lead to the pathogenesis of HF because of their effects on the heart and peripheral circulation. The “smoker’s paradox” showed associations between improvements in short-term acute myocardial infarction (MI) and smokers via activation of α7 nicotinic acetylcholine receptor (α7 nAChR) that can inhibit inflammatory responses in HF. Studies showed that the vagus nerve can modulate these inflammatory responses by activating the cholinergic anti-inflammatory pathway via stimulation of α7 nAChR. Hence, stimulation of α7 nAChR with specific agonists can be a potential therapeutic target for HF because it can inhibit pro-inflammatory responses. In this study, the anti-inflammatory effects of 3-(2,4-dimethoxybenzylident)-anabaseine (GTS-21), a partial agonist of α7 nAChR, were observed in an in vivo zebrafish model for HF. For four consecutive days, the zebrafishes were pre-treated with GTS-21 (0.113 μM) for 20 minutes per day. On the fourth day after pre-treatment with GTS-21, the zebrafishes were induced with MI by oligo-[2-(2-ethoxy)- ethoxyethyl)-guanidinium-chloride] (PGH) and survival was recorded. Using reverse transcription PCR (rt-PCR) for analysis, results showed that pre-treatment with GTS-21 modified the gene regulatory protein levels and reduced cytokine expression in the myocardium tissue. Other α7 nAChR agonists were investigated for their potential therapeutic effect in inhibiting inflammatory responses, but GTS-21 was more efficacious in inhibiting cytokine expression. Thus, GTS-21 may be used as a novel therapeutic for HF.