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

Fernández‐Hernando, Carlos; Yu, Jun; Dávalos, Alberto; Prendergast, Jay S.; Sessa, William C.

doi:10.2353/ajpath.2010.091287

Cited by 95 publications

(76 citation statements)

References 27 publications

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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: 75%

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: 75%

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

et al. 2015

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“…Less LDL penetration and greater NO production was seen in Cav-1 Ϫ/Ϫ mice (522). Endothelial-specific overexpression increased atherosclerosis (521). Even greater reduction in atherosclerosis seen in a more recent study (477).…”

Section: Calcium Signaling Ion Channels and Weibel-palade Body Exocmentioning

confidence: 92%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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“…In their study published in the current issue of The American Journal of Pathology, Ferná ndez-Hernando et al 17 have demonstrated the important if not essential function of caveolin-1 in the development of atherosclerosis. Their data confirmed previous findings they had obtained using caveolin-1-deficient mice that were bred with mice overexpressing caveolin-1 specifically in endothelial cells.…”

Section: An Essential Role For Endothelial Caveolin-1 In the Developmmentioning

confidence: 97%

Endothelial Caveolae and Caveolin-1 as Key Regulators of Atherosclerosis

Frank¹

2010

The American Journal of Pathology

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

Cited by 95 publications

References 27 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

Molecular Biology of Atherosclerosis

Endothelial Caveolae and Caveolin-1 as Key Regulators of Atherosclerosis

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