Abstract
Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1-/-AdipoR2-/-) on atherosclerosis. However, we made the interesting observation that AdipoR1 -/- AdipoR2 -/- leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE -/-) mice. AdipoR2-/-ApoE-/- mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2 +/+ApoE-/- littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2-/-ApoE-/- mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2-/-ApoE-/- mice compared with AdipoR2+/+ApoE-/- controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.
Highlights
Adiponectin is one of the most abundant factors secreted from adipocytes [1,2,3,4]
In order to study the effects of combined adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) deficiency on atherosclerosis during ApoE deficiency, we first wanted to produce AdipoR1-/-AdipoR2-/- mice
In this study in male mice, we could for the first time show that knocking out both AdipoR1 and AdipoR2 results in embryonic lethality demonstrating the critical importance of these receptors and the adiponectin signalling system during embryonic development
Summary
Several studies in experimental animals have demonstrated anti-diabetic [11,12,13] and anti-atherosclerotic [12,13,14,15] effects of adiponectin. Adiponectin can protect the heart from ischemia-reperfusion injury [16] and can act as an endogenous anti-thrombotic factor [17]. The anti-atherosclerotic effects of adiponectin have been demonstrated at several stages in plaque development, ranging from endothelial dysfunction and plaque initiation to plaque progression and rupture (reviewed in 18). In vitro studies have shown that adiponectin suppresses monocyte adhesion and expression of endothelial cell adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin [7]. Studies have shown that adiponectin can induce cholesterol efflux from macrophages via upregulation of the ATP-binding cassette transporter ABCA1 [20,21]
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