Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation

Abstract

Background-Atherosclerosis is driven by synergistic interactions between pathological biomechanical, inflammatory and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide synthase (eNOS) and increased production of nitric oxide (NO), reduced inflammation and low-density lipoprotein (LDL) trafficking. However, the contribution of eNOS activation and NO production in the athero-protection of Cav1 and the exact mechanisms by which Cav1/caveolae controls the pathogenesis of diet-induced atherosclerosis are still not clear. Methods-Triple knockout mouse lacking expression of eNOS, Cav1 and Ldlr were generated to explore the role of NO production in Cav1-dependent atheo-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix (ECM) remodeling and vascular inflammation were studied both in vitro and in vivo using a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. Results-We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr −/− eNOS −/− mice, demonstrating that athero-suppression is independent of increased NO production. Instead, we find that absence of Cav1/caveolae inhibited LDL transport across the endothelium, pro-atherogenic fibronectin deposition, and disturbed flow-mediated endothelial cell (EC) inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flowdependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and athero-resistant areas of the aortic arch even in wild-type mice. Conclusions-The above findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic and inflammatory pathways independent of endothelial eNOS activation and NO production.

Role of Caveolin-1 in Diabetes and Its Complications

“…They have crossed CAV1-/with eNOS-/-mice into a proatherogenic background and found that CAV1 controls proatherogenic responses of endothelial cells to disturbed blood flow, including lipid trafficking, extracellular matrix (ECM) remodeling, and inflammatory signaling in early-stage ath-erosclerotic lesions. CAV1 also promotes proatherogenic matrix deposition leading to endothelial cell activation in atheroprone regions of the aorta [128]. Hence, these data indicate that CAV1-based therapeutics should be further studied to alleviate the burden of diabetic complications.…”

Interplay Between Statins, Cav1 (Caveolin-1), and Aldosterone

“… 28 , 29 Our findings showed no significant difference in LDL level by Cav1 genotype, although preclinical studies have shown that Cav1 may be involved in the regulation of lipoprotein metabolism and transcytosis of LDL. 30 , 31 Future prospective randomized controlled studies are needed to assess the impact of Cav1 genotype on the effectiveness of statins in lowering LDL.…”

Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

“…d-PDMP might exert both anti-inflammatory and anti-oxidative functions via decreased ERK activation. Since increased lipid-raft levels are associated with inflammation, we measured the expression of Caveolin-1, a raft-specific marker [7,25]. A reduction in Caveolin-1 protein was found in d-PDMP-treated aortas ( Figure 5L).…”