The macrophage is the major cell type responsible for choles

The macrophage is the major cell type responsible for cholesterol uptake and metabolism associated with the initiation and progression of atherosclerosis in focal areas of the arterial subendothelial space. In advanced atherosclerotic lesions of cardiovascular disease, cholesterol-induced macrophage apoptosis generates cell debris that can promote the formation of the necrotic core of the atherosclerotic plaque [108]. The lipid-rich plaques may become unstable, increasing the potential risk of thrombosis, cardiac arrest and death. Although the mechanisms regulating cholesterol uptake, efflux, esterification and storage in cytoplasmic neutral lipid droplets in macrophages have been well-characterized, a role for ABCA2 in modulating macrophage response to excess sterol loading, free cholesterol trafficking from the LE/LY compartment to the endoplasmic to the ER and apoptosis has not been fully elucidated. Excess free cholesterol is toxic to macrophages [109], [110], [111], [112], [113]. The principal site of cholesterol-induced toxicity in macrophages is the endoplasmic reticulum (ER), through activation of the unfolded protein response (UPR) and initiation of apoptosis [112]. In cell culture, sterol loading of macrophages with acetylated LDL (AcLDL) together with a pharmacological inhibition of ACAT re-esterification of free cholesterol to cholesteryl esters produced an increase in free cholesterol-induced toxicity [113]. Significantly, addition of U18666A or progesterone, inhibitors of cholesterol transport from the LE/LY, reduced cholesterol-induced toxicity. Importantly, macrophages from mice, nrf2 keap1 for a loss of function mutation in the Niemann-Pick type C1 (NPC1) gene, exhibited reduced cholesterol trafficking from the LE/LY to the ER and were more resistant to cholesterol-induced apoptosis [112]. This in vivo finding suggests that cholesterol trafficking from the LE/LY to the endoplasmic reticulum is a key pathway for modulating cholesterol-induced toxicity in macrophages. ABCA2 may function to modulate cholesterol trafficking from the LE/LY to the ER in macrophages to reduce free cholesterol induced toxicity under conditions of high plasma lipoprotein-derived cholesterol. A possible mechanistic role for ABCA2 in the etiology of cardiovascular disease was suggested by a study describing the effects of ABCA2 deletion in ABCA2 knockout macrophages generated in LDL receptor knockout mice [114]. They reported diminished lesion size in the aortic root and descending thoracic aorta, and a 3-fold increase in apoptotic cells. While wild-type macrophages developed filipin positive droplets in lysosomal-like compartments, corresponding to free cholesterol accumulation, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of free cholesterol over peripheral regions, as well as an accumulation of neutral sterols in lipid droplets. Finally, in oxLDL-loaded macrophages, a source of lipoprotein-derived cholesterol, apoptosis was increased 2.7-fold. These studies provide additional evidence of a key role for macrophage ABCA2 in modulating free cholesterol sequestration in the LE/LY that may be important for the initiation and progression of cardiovascular disease.
Conclusions & perspectives
Introduction It has been reported that the smooth muscle of the bladder base contains α-adrenoceptors facilitating bladder outlet contraction while β-adrenoceptors are found in the lateral wall, linked to bladder relaxation (Andersson and Arner, 2004; Levin and Wein, 1979). mRNA for all three β-adrenoceptor isoforms (β1, β2, β3) has been identified in the detrusor (Fujimura et al., 1999; Seguchi et al., 1998). Using selective β-adrenoceptor agonists, it was proposed that the β3-adrenoceptor isoform was the most relevant in human detrusor relaxation (Igawa et al., 1998; Svalo et al., 2013). These conclusions led to the idea that the β3-adrenoceptor system would be a potential therapeutic target for the management of bladder pathology: overactive bladder (OAB) (Fujimura et al., 1999; Sacco and Bientinesi, 2012). Indeed, drugs such as mirabegron have been shown to reduce symptoms of urge and frequency and to improve quality of life scores in patients with OAB (Sacco and Bientinesi, 2012).