Genetic Evidence Supporting a Critical Role of Endothelial Caveolin-1 during the Progression of Atherosclerosis

Fernández‐Hernando, Carlos; Yu, Jun; Suárez, Yajaira; Rahner, Christoph; Dávalos, Alberto; Lasunción, Miguel A.; Sessa, William C.

doi:10.1016/j.cmet.2009.06.003

Cited by 162 publications

(171 citation statements)

References 33 publications

(34 reference statements)

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“…Another key finding of our work stems from the observation that CavNOxin-induced NO upregulation was able to attenuate aortic and endothelial VCAM-1 expression, which correlated closely with the reduction in leukocyte/monocyte adhesion to the vascular wall and to cultured endothelial cells in diabetic and inflammatory (TNF-a) settings, lending credence to previous studies that demonstrated decreased leukocyte recruitment and VCAM-1 expression in Cav-1 KO tissues (38)(39)(40). Furthermore, increased eNOS activity has been associated with the downregulation of adhesion molecules, in particular VCAM-1 (19), and our data suggest that this can be achieved specifically through endogenous eNOS in a compensatory manner because hyperglycemia is a potent inducer of leukocyte-endothelial interactions (13,41).…”

Section: Discussionsupporting

confidence: 58%

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

et al. 2015

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Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ∼84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.Diabetes is widely regarded as an independent risk factor for the development of cardiovascular diseases, with ;80% of cardiovascular mortality and morbidity being linked to macrovascular complications, such as atherosclerosis (1-3). The increased risk of development of vascular complications in individuals with type 1 (T1D) or type 2 diabetes (T2D) occurs despite intensive glycemic control, stressing the need for novel approaches to lessen the burden of diabetes-mediated macrovascular injury (4).The vascular endothelium plays a crucial role in diabetesassociated atherosclerosis through the regulation of vessel permeability, inflammation, coordination of leukocyte trafficking, and thrombosis (1,5). Indeed, the function of the vascular endothelium is significantly impaired during diabetes, a phenomena termed endothelial dysfunction and characterized by the reduced bioavailability of an important endothelial cell mediator, nitric oxide (NO). Such chronic attenuation of endothelial-derived NO release promotes platelet and leukocyte activation and adhesion, compromises endothelial cell barrier integrity, and causes the upregulation of proinflammatory genes (6-8). Moreover, reduced NO-dependent vasodilation and increased leukocyte adhesion to the endothelium, both of which are hallmarks of endothelial dysfunction, have been observed in patients with diabetes and diabetic animal models (9-12). Similarly, in cultured endothelial cells exposed to high glucose, lowered endothelial NO synthase (eNOS)-derived NO release was observed (13-15). In...

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Section: Discussionsupporting

confidence: 58%

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

et al. 2015

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“…It was reported that LDL-derived cholesterol, the major component of atherosclerotic plaque, enters the subendothelial space through the caveolaemediated pathway (Sun et al 2010). Results from cav-1 (caveolin-1, the key structural protein of caveolae)-deficient mice indicated that cav-1 in endothelium is essential in the translocation of LDL-derived cholesterol into the vessel wall and in the development of atherosclerosis, and this result was further confirmed in apoE-/-mice (Fernandez-Hernando et al 2009. On the other side, vascular endothelial growth factor (VEGF), one of the strongest hyperpermeability inducers (Senger et al 1990), plays a critical role in both physiological and pathological hyperpermeability (Bates and Harper 2002).…”

Section: Introductionsupporting

confidence: 55%

“…On the other side, Cav-1 is the key structural protein of caveolae (Drab et al 2001). Reexpression of endothelial cav-1 in cav-/-mice demonstrated that cav-1 is indispensable to the transportation of LDL-derived cholesterol to the subendothelial space (Fernandez-Hernando et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway

Tian

Zhang

et al. 2012

Genes Nutr

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Endothelial hyperpermeability induced by hyperglycemia is the initial step in the development of atherosclerosis, one of the most serious cardiovascular complications in diabetes. In the present study, we investigated the effects of resveratrol (RSV), a bioactive ingredient extracted from Chinese herb rhizoma polygonum cuspidatum, on permeability in vitro and the molecular mechanisms involved. Permeability was assessed by the efflux of fluorescein isothiocyanate (FITC)-dextran permeated through the monolayer endothelial cells (ECs). The mRNA levels, protein expressions, and secretions were measured by quantitative real-time PCR, western blot, and ELISA, respectively. Increased permeability and caveolin-1 (cav-1) expression were observed in monolayer ECs exposed to high glucose. Resveratrol treatment alleviated the hyperpermeability and the overexpression of cav-1 induced by high glucose in a dose-dependent manner. b-Cyclodextrin, a structural inhibitor of caveolae, reduced the hyperpermeability caused by high glucose. Resveratrol also down-regulated the increased expressions of vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR, or VEGF receptor-2) induced by high glucose. Inhibition of VEGF/KDR pathway by using SU5416, a selective inhibitor of KDR, alleviated the hyperpermeability and the cav-1 overexpression induced by high glucose. The above results demonstrate that RSV ameliorates caveolae-mediated hyperpermeability induced by high glucose via VEGF/KDR pathway.

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“…10 -12 In the cardiovascular system, caveolae and Cav-1 show an important role in the proliferation and migration of smooth muscle cells, 13 regulation of NO production and vascular permeability, 8,14 angiogenesis, [15][16][17] and atherosclerosis. 18,19 Cav-1-deficient mice develop cardiac hypertrophy, hypercholesterolemia, and hypertriglyceridemia and have increased tumor microvascular permeability, angiogenesis, and growth. 17 Interestingly, the absence of Cav-1 reduces the progression of atherosclerosis.…”

mentioning

confidence: 99%

“…19 Very recently, we showed, using a genetic model, that endo-thelial caveolae are essential for the progression of atherosclerosis. 18 Mechanistically, endothelial Cav-1 and caveolae are critical for LDL infiltration in the artery wall, NO production, and macrophage accumulation, all events necessary for atherogenesis. 18 Although Cav-1-null mice are useful to delineate the importance of caveolae in atherosclerosis, there are additional problems that are difficult to dissect, because loss of Cav-1 abolishes both caveolae organelles as well as Cav-1-mediated signaling pathways.…”

mentioning

confidence: 99%

Endothelial-Specific Overexpression of Caveolin-1 Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

Fernández‐Hernando

Dávalos

et al. 2010

The American Journal of Pathology

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Caveolin-1 (Cav-1) is the major structural protein essential to the formation of the caveolae in endothelial cells. Genetic ablation of Cav-1 on an apolipoprotein E knockout background inhibits the progression of atherosclerosis, whereas re-expression of Cav-1 in the endothelium promotes lesion expansion. Although Cav-1-null mice are useful to delineate the importance of caveolae in atherosclerosis, there are additional problems that are difficult to dissect because loss of Cav-1 abolishes both the caveolae organelle as well as the Cav-1-mediated signaling pathways. To study how Cav-1 influences the progression of atherosclerosis in mice with caveolae, we generated a transgenic mouse that overexpresses Cav-1 in the endothelial cells in an apolipoprotein E-deficient background. We found that endothelial-specific overexpression of Cav-1 enhanced the progression of atherosclerosis in mice. Mechanistically, overexpression of Cav-1 reduced endothelial cell proliferation, migration, and nitric oxide production in vitro and increased expression of vascular cell adhesion molecule-1 in vivo. (Am J

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Genetic Evidence Supporting a Critical Role of Endothelial Caveolin-1 during the Progression of Atherosclerosis

Cited by 162 publications

References 33 publications

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis

Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway

Endothelial-Specific Overexpression of Caveolin-1 Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice

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