Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the Show more
Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Show less
The CD36 selective ligand, EP 80317, features potent anti-atherosclerotic and hypocholesterolemic effects that are associated with an increase in macrophage cholesterol efflux through the activation o Show more
The CD36 selective ligand, EP 80317, features potent anti-atherosclerotic and hypocholesterolemic effects that are associated with an increase in macrophage cholesterol efflux through the activation of the peroxisome proliferator-activated receptor γ-liver X receptor α (LXRα)-ATP-binding cassette (ABC) transporter pathway. Cholesterol efflux is the first step of reverse cholesterol transport (RCT). However, whether EP 80317 exerts its hypocholesterolemic and anti-atherosclerotic activity through RCT in vivo has yet to be determined. In the present study, we investigated the effects of EP 80317 on RCT, in particular on macrophage-to-feces RCT and the expression of selected genes associated with hepatic cholesterol metabolism and intestinal cholesterol transport. Reverse cholesterol transport was assessed following the intraperitoneal injection of [(3)H]-cholesterol-labelled J774 macrophages to hypercholesterolemic apoE- and apoE/CD36 double-deficient mice that had been treated for 12 weeks with EP 80317. Forty-eight hours after the administration of [(3)H]-cholesterol-labelled cells, blood, liver, intestines and feces were harvested. The radioactivity recovered in the feces (cholesterol and bile acid combined) was significantly increased by 311% (P = 0.0259) in EP 80317-treated mice compared with that found in vehicle-treated mice despite no significant change in [(3)H]-tracer recovery in plasma between groups. Whereas the mRNA levels of LXRα in the gut were significantly upregulated, mRNA and protein levels of the Niemann-Pick C1-like 1 protein (NPC1L1) transporter, a LXRα target which regulates intestinal cholesterol absorption, were downregulated in EP 80317-treated mice. In contrast, neither mRNA nor protein levels of investigated transporters and receptors were modulated in the small intestine of double-deficient mice, nor was the fecal recovery of radioactivity. No change was observed in targeted genes in liver of either apoE- or apoE/CD36 double-deficient mice after a chronic treatment with EP 80317. This study shows that EP 80317 elicits macrophage-to-feces reverse cholesterol transport in a manner dependent on CD36 expression. This effect is associated with the upregulation of LXRα and the downregulation of NPC1L1 expression. Show less