Proposed model illustrating the possible role of the α7nAchr and the cholinergic anti-inflammatory reflex in atherosclerosis. Inflammatory stimuli promote macrophage accumulation in both the intima (from the systemic circulation) and adventitia (from the vasa vasorum) of the artery wall. The vagus nerve innervates the adventitial layer of epicardial coronary arteries and the aorta. Inflammatory cytokines produced by arterial wall macrophages may bind and activate afferent vagal fibers in the adventitia. Subsequent activation of efferent vagal fibers results in the release of
Entinostat (Ach) in the adventitia. Ach can bind to α7nAchr on adventitial macrophages, or diffuse across the media to the intima where it can bind to intimal macrophage α7nAchr and inhibit inflammatory cytokine production (IL-1, IL-6, CRP) by these cells, reduce CD36 expression, reduce macrophage cholesterol content, and increase PON2 expression. The resulting decrease in inflammatory cytokine production and cholesterol uptake by
macrophages will inhibit foam cell formation, and hence, atherosclerosis. In the absence of the α7nAchr, inflammatory cytokine production by intimal or adventitial macrophages will persist, thus promoting atherosclerosis. Dashed arrows represent movement of cells, cytokines, proteins, or neurotransmitters between the different layers of the artery wall during atherogenesis.
