Investigation of expression and function of alpha-7 nicotinic receptor as an anti-inflammatory target in atherosclerosis

Abstract

Atherosclerosis is a cardiovascular disease, the leading cause of mortality with an astonishing increase in death rate worldwide according to WHO. This is twice as many death cases caused by cancer. Atherosclerosis is a chronic inflammatory disease resulting in intense complications such as either a myocardial infarction or a stroke. It is deemed as inflammation process triggered by innate immune cells with response to pathogen invasion, tissue injury etc. The cholinergic anti-inflammatory pathway is a key regulator of inflammation by suppressing cytokine activity. It functions as a neural circuit aiding in immunomodulation process, reacting to and tuning inflammation to optimal rate. The pathway comprises two main components, the vagus nerve and neurotransmitter acetylcholine. Stimulation of efferent vagus nerve releases acetylcholine which later interacts with alpha-7 nicotinic receptor (α7nAChR) on macrophages. This binding leads to activation of intracellular signal transduction later inhibiting pro-inflammatory cytokine release. Not much is known about function of α7nAChR in atherosclerosis. However few researches suggested their importance in anti-inflammation role. Thus the overall aim of this thesis was to detect and evaluate expression and function of α7nAChR using RT-PCR technique in healthy and atherosclerosis prone mouse aortas. Receptor stimulation in-vitro is carried out using nicotine, a potent ligand for α7nAChR. LPS stimulation was performed with or without combining effect of nicotine to evaluate receptor function in attenuating cytokine release. The result indicated the expression of α7nAChR in normal and atherosclerotic prone samples with absence in α7R knockout mice samples suggesting presence of receptor for further evaluation on its function. The in-vitro stimulation failed to explain the function of receptor the in reducing released cytokines. Thus the report provides evidence implicating expression pattern of receptor in healthy and atherosclerotic samples. Further experiments are required to elucidate function of receptor on inflammatory profile of atherosclerotic plaque.