Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance

Féron, Olivier; Dessy, Chantal; Desager, Jean‐Pierre; Balligand, Jean‐Luc

doi:10.1161/01.cir.103.1.113

Cited by 394 publications

(248 citation statements)

References 22 publications

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“…Western blots revealed no overt change in the expression levels of NO synthases (i.e., eNOS and inducible NOS) in the heart and lung from the cav-1 Ϫ/Ϫ mouse (data not shown), suggesting that the high NO level was most likely caused by an elevation in eNOS activity resulting in massive NO production. This finding is in agreement with recent in vitro studies that hypercholesterolemia decreased NO production by promoting the interaction of Cav-1 and eNOS and a decrease in Cav-1 abundance through atorvastatin, an inhibitor of hydroxymethylglutaryl-CoA reductase, can promote eNOS activation (26,27).…”

Section: Cav-1 Deficiency Causes Pulmonary Hypertension and Resultingsupporting

confidence: 93%

“…The consequence for eNOS function of this cholesterol-induced increase in Caveolin abundance is a marked decline in basal NO release, suggesting that the equilibrium between eNOS bound to Caveolin and Caveolinfree eNOS determines the basal component of eNOS-dependent NO release in endothelial cells. This interaction may be required to protect the cell from undesired, potentially cytoxic, or nonphysiological bursts of NO in response to small fluctuation in intracellular calcium (26,27).…”

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confidence: 99%

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Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Zhao

Liu

Stan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

430

382

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Caveolins are important components of caveolae, which have been implicated in vesicular trafficking and signal transduction. To investigate the in vivo significance of Caveolins in mammals, we generated mice deficient in the caveolin-1 (cav-1) gene and have shown that, in the absence of Cav-1, no caveolae structures were observed in several nonmuscle cell types. Although cav-1 ؊/؊ mice are viable, histological examination and echocardiography identified a spectrum of characteristics of dilated cardiomyopathy in the left ventricular chamber of the cav-1-deficient hearts, including an enlarged ventricular chamber diameter, thin posterior wall, and decreased contractility. These animals also have marked right ventricular hypertrophy, suggesting a chronic increase in pulmonary artery pressure. Direct measurement of pulmonary artery pressure and histological analysis revealed that the cav-1 ؊/؊ mice exhibit pulmonary hypertension, which may contribute to the right ventricle hypertrophy. In addition, the loss of Cav-1 leads to a dramatic increase in systemic NO levels. Our studies provided in vivo evidence that cav-1 is essential for the control of systemic NO levels and normal cardiopulmonary function.

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Section: Cav-1 Deficiency Causes Pulmonary Hypertension and Resultingsupporting

confidence: 93%

mentioning

confidence: 99%

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Zhao

Liu

Stan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

430

382

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“…Having demonstrated that augmenting KLF2 levels within the Treg compartment is sufficient to promote peripheral tolerance, we next tested if this event could be replicated by simvastatin. Of note, statins have an immunosuppressive effect on endothelial cells, including decreased MHC class II expression, decreased expression of P-selectin and CD40, increased surface expression of complement inhibitory molecules, and increased production of nitric oxide (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Because the endothelial compartment contributes to symptoms of aGVHD (42)(43)(44)(45), these pleiotropic effects precluded the systemic use of simvastatin to test Treg-mediated tolerance.…”

Section: Increased Klf2 Expression Within the Treg Compartment Augmentsmentioning

confidence: 99%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.

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“…Statins have been shown to improve NO synthesis by mechanisms unrelated to changes in serum LDL levels, including upregulation of eNOS expression 73 and reduced superoxide formation. 74,75 Additionally, statins stimulate endothelial NO production through a dramatic reduction in plasma membrane caveolin levels 76 (Figure 1). By interfering with cholesterol biosynthesis and lowering plasma membrane cholesterol levels, atorvastatin was shown to attenuate the expression of caveolin-1 ( Figure 5).…”

Section: Effects Of Hmg-coa Reductase Inhibitors On Cholesterol Micromentioning

confidence: 99%

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

2004

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Abstract-Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function.(1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.

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Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance

Cited by 394 publications

References 22 publications

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

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