Abstract
The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr–/– rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.
Highlights
As a chronic disease affecting arteries, atherosclerosis is characterized by lumen narrowing progressively developed from gradual expansion of lesions, which may eventually lead to myocardial infarction or stroke
Phenotypes associated with atherosclerosis development including lipid metabolism, oxidative stress and macrophages were compared between G2a−/− and wild type (WT) rats
As in WT, the absence of G2A in Ldlr−/− rats greatly up-regulated iNOS mRNA expression, both in the aorta and oxidized low-density lipoproteins (oxLDL) stimulated macrophages, suggesting stress associated with increased blood oxLDL and oxLDL uptake
Summary
As a chronic disease affecting arteries, atherosclerosis is characterized by lumen narrowing progressively developed from gradual expansion of lesions, which may eventually lead to myocardial infarction or stroke. Rat G2A Deficiency Aggravates Atherosclerosis lipid metabolism leads to immune cell infiltration and aggravated lesions in the arterial wall (Moore and Tabas, 2011; Shalhoub et al, 2011; Fogelstrand and Boren, 2012; van Diepen et al, 2013). The number of infiltrated macrophages and their location at plaque rupture-sensitive sites is related to plaque vulnerability (Davies et al, 1993). As part of their general homeostatic scavenging function, macrophages could consume toxic lipids, such as oxidized low-density lipoproteins (oxLDL) (Acton et al, 1996). The pathological mechanism of atherosclerosis suggest that, lipid-lowering therapy represents the mainstream strategy at the moment, the possible combination of restoring imbalanced immunity could become a promising new goal for combating the disease
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