Nitric Oxide-Donating Statins Upgrade the Benefits of Lipid-Lowering in Vascular Inflammation by Desensitizing Neutrophil Activation

Excerpt

Cardiovascular events are the leading cause for morbidity and mortality in Western societies. Clinical manifestations such as myocardial infarction and stroke mainly rely on the development and progression of atherosclerosis, which, in terms of identifying promising therapeutic targets, requires detailed understanding of its pathophysiology and underlying cellular as well as molecular mechanisms [1, 2]. Atherosclerosis has widely been accepted to be a chronic inflammatory disease of the arterial wall [1, 2]. Initially promoted by multifaceted parameters such as modified low density lipoprotein (LDL) or altered flow, it is characterized by endothelial dysfunction. Activation of endothelial cells subsequently launches a cascade of self-amplifying inflammatory processes such as expression of chemokines, cytokines and adhesion molecules, all of which then contribute to leukocyte activation, adhesion, arrest and transmigration [3]. Besides lymphocytes, which can be regularly detected in atherosclerotic plaques [1, 3], monocytes are appreciated to be the most abundant subset to enter atherosclerotic lesions already in early stages and also during the course of lesion progression [3]. Hence, lesion growth is primarily sustained by constant influx of classical monocytes [4, 5]. Once monocytes have entered the lesion they differentiate into macrophages and after uptake of oxidized LDL into foam cells. However, throughout the past years it has become evident that a so far under-appreciated leukocyte subset, namely the polymorphnuclear neutrophil, is crucially involved in early atherosclerotic development [6, 7]. Lately, refined staining techniques allowed for sensitive detection of neutrophils in murine and human atherosclerotic plaque specimens. The use of antibodies to Ly6G specifically expressed on mouse neutrophils enabled the detection in early lesions as well as in rupture-prone atherosclerotic plaques [7, 8]. Unlike other leukocyte subsets, neutrophils could be identified only in rare numbers, which might be the reason why their ability to orchestrate atherosclerosis development has been considered controversial for decades. Initial implications for neutrophil-driven pro-atherogenic functions stem from mouse models with neutrophilia, due to deficiency in either the neutrophil-homeostasis regulating chemokine receptor CXCR4 or the hematopoietic interferon regulatory factor 8 (IRF8). Both display a massive expansion of circulating neutrophils accompanied by significantly increased atherosclerotic lesion sizes [9, 10]. Another study demonstrates that circulating neutrophil counts directly correlate with the extent of atherosclerosis and depletion of neutrophils during early stages widely protects from lesion formation due to impaired accumulation of monocytes and macrophages [7], thus being in line with observations made in microvascular models of inflammation [11, 12]. Recent work identified mechanisms underlying neutrophil-mediated atherogenesis thereby proving that neutrophil-derived cathelicidin (human: LL37; mouse: CRAMP) is released from emigrated neutrophils and reversely transported across the endothelium, thus mediating adhesion of classical monocytes via formylated peptide receptor 2 (FPR2) [13]. In line, atherosclerotic mice deficient of CRAMP displayed reduced lesion sizes [14]. Hence, neutrophil-dependent inflammatory processes shall be taken into account when designing tools for future treatment of atherosclerosis. …