The alpha 7 nicotinic acetylcholine receptor in cardiovascular disease

Abstract

The alpha 7 acetylcholine nicotinic receptors (α7nAChRs) are expressed on human leukocytes and regulate inflammation. Consequently, the α7nAChRs are potential pharmacological targets for several inflammatory diseases. Numerous specific agonists have been developed to explore whether stimulation of the α7nAChRs can affect the immune response. Meanwhile, the exact mechanism whereby the α7nAChRs act remains unknown. The overall aim of this thesis is to investigate how the α7nAChRs can modulate inflammation and thereby influence cardiovascular disease. In Paper I, we found that stimulation of the α7nAChRs with AZ6983 inhibits atherosclerosis in mice. In Paper II, we showed promising anti-inflammatory effects of PHA 568487 in mice in the air pouch model of inflammation, however, no effect was seen in infarct size and cardiac function in the permanent ligation model of myocardial infarction. In Paper III, we showed that stimulation of the α7nAChRs with PHA 568487 dampened inflammation in immune cells from healthy individuals as well as in immune cells from patients with newly discovered coronary artery disease, with a more pronounced effect in the patient group. Finally, in Paper IV, we found a clear sex difference in the anti-inflammatory effect of α7nAChRs stimulation, since PHA 568487 prominently reduced the secretion of cytokines in immune cells extracted from men. Taken together, our results confirm the anti-inflammatory potential of α7nAChRs stimulation in human immune cells in vitro as well as in animals in vivo.