Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation

Mirza, M. B.; Yuan, Jun; Gao, Xiao Pei; Garrean, Sean; Brovkovych, Viktor; Malik, Asrar B.; Tiruppathì, Chinnaswamy; Zhao, You Yang

doi:10.2353/ajpath.2010.091088

Cited by 69 publications

(90 citation statements)

References 44 publications

(52 reference statements)

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“…26,43 Indeed, reduced angiogenesis in the absence of eNOS is confirmed in our experiments from the in vitro, ex vivo and in vivo angiogenic phenotype of Cav ϩ/ϩ eNOS Ϫ/Ϫ mice, and substantiated by the reduced angiogenesis in wild-type mice treated with L-NAME. In agreement with our results, excess NO production has been shown to mediate other aspects of the phenotype of caveolin-1 knock-out mice, namely pulmonary hypertension 44,45 even though NO per se is a potent vasodilator, reduction of innate immunity 46 even though NO has direct and indirect antimicrobial activities, and cardiomyopathy. 47 One mechanism for these consequences of increased eNOS activity in caveolin-1-null mice has been proposed to be the formation of peroxinitrite when NO is combined to superoxide, and the subsequent deleterious nitration reactions affecting functional proteins such as protein kinase G 41 or interleukin-1 receptor-associated kinase.…”

Section: Discussionsupporting

confidence: 80%

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

Morais

Ebrahem

Anand‐Apte

et al. 2012

The American Journal of Pathology

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Caveolin-1 is an essential structural protein of caveolae, specialized plasma membrane organelles highly abundant in endothelial cells, where they regulate multiple functions including angiogenesis. Caveolin-1 exerts a tonic inhibition of endothelial nitric oxide synthase (eNOS) activity. Accordingly, caveolin-1 gene-disrupted mice have enhanced eNOS activity as well as increased systemic nitric oxide (NO) levels. We hypothesized that excess eNOS activity, secondary to caveolin deficiency, would mediate the decreased angiogenesis observed in caveolin-1 gene-disrupted mice. We tested tumor angiogenesis in mice lacking either one or both proteins, using in vitro, ex vivo, and in vivo assays. We show that endothelial cell migration, tube formation, cell sprouting from aortic rings, tumor growth, and angiogenesis are all significantly impaired in both caveolin-1-null and eNOSnull mice. We further show that these parameters were either partially or fully restored in double knockout mice that lack both caveolin-1 and eNOS. Furthermore, the effects of genetic ablation of eNOS are mimicked by the administration of the NOS inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME), including the reversal of the caveolin-1-null mouse angiogenic phenotype. This study is the first to demonstrate the detrimental effects of unregulated eNOS activity on angiogenesis, and shows that impaired tumor angiogenesis in caveolin-1-null mice is, at least in part, the result of enhanced eNOS activity.

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Section: Discussionsupporting

confidence: 80%

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

Morais

Ebrahem

Anand‐Apte

et al. 2012

The American Journal of Pathology

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“…It has been shown that cav-1 participates in the rapid signaling elicited by the hormone (54). Cav-1, the scaffolding protein of caveolae, has also been shown to play an important role in host defense and inflammation (55). Increased cav-1 in the heart noted in our results suggests that the tissues were greatly damaged after having undergoing CPZ-induced toxicity.…”

Section: Discussionsupporting

confidence: 57%

E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity

Huang

Liu

2011

Mol Med Report

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Abstract. Heart damage induced by chlorpromazine (CPZ) toxicity is associated with changes in the expression of various enzymes and proteins. This study aimed to investigate CPZ-induced alterations in cardiac E-cadherin and caveolin-1 (cav-1) after CPZ administration. Male Wistar rats were randomly divided into two groups: a control group and a CPZ group. The CPZ group was administered CPZ intraperitoneally at a single dose of 10 mg/kg for 21 days; the controls were given the same amount of saline via the same route. On Day 22, the rats were anesthetized, and a thoracotomy was performed in all animals. Immunohistochemical analysis was performed to evaluate protein expression of E-cadherin and cav-1. Sections were analyzed by digital image analysis. Results of the present study revealed that cardiac protein expression of E-cadherin and cav-1 was altered after CPZ-induced toxicity in the rat. The expression of E-cadherin was significantly reduced, while expression of cav-1 was significantly increased after CPZ treatment, as supported by integrated optical density analysis, compared with the control (P<0.05). The current findings indicate that such changes in the expression of E-cadherin and cav-1 may be reflected in abnormal cardiac function, and these proteins may be useful in revealing the mechanisms underlying CPZ-induced toxicity and may also provide additional insight for further research.

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“…In these disease models, the functions of Cav-1 in disease pathogenesis appear to be mediated, at least in part, by autophagy. In lipopolysaccharide (LPS)-induced lung inflammation and sepsis models, deletion of Cav-1 resulted in decreased production of inflammatory mediators and animal mortality (10,27), but whether this function of Cav-1 is due to autophagy remains unclear, although recently autophagy has been shown to suppress LPS-induced inflammation and LC3B-deficient mice were more susceptible to LPS-induced mortality (31).…”

Section: Discussionmentioning

confidence: 99%

Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells

Chen

Cao

Zhou

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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AM, Shen H. Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 306: L1016 -L1025, 2014. First published April 11, 2014 doi:10.1152/ajplung.00268.2013.-Autophagy plays a pivotal role in cellular homeostasis and adaptation to adverse environments, although the regulation of this process remains incompletely understood. We have recently observed that caveolin-1 (Cav-1), a major constituent of lipid rafts on plasma membrane, can regulate autophagy in cigarette smoking-induced injury of lung epithelium, although the underlying molecular mechanisms remain incompletely understood. In the present study we found that Cav-1 interacted with and regulated the expression of ATG12-ATG5, an ubiquitin-like conjugation system crucial for autophagosome formation, in lung epithelial Beas-2B cells. Deletion of Cav-1 increased basal and starvation-induced levels of ATG12-ATG5 and autophagy. Biochemical analyses revealed that Cav-1 interacted with ATG5, ATG12, and their active complex ATG12-ATG5. Overexpression of ATG5 or ATG12 increased their interactions with Cav-1, the formation of ATG12-ATG5 conjugate, and the subsequent basal levels of autophagy but resulted in decreased interactions between Cav-1 and another molecule. Knockdown of ATG12 enhanced the ATG5-Cav-1 interaction. Mutation of the Cav-1 binding motif on ATG12 disrupted their interaction and further augmented autophagy. Cav-1 also regulated the expression of ATG16L, another autophagy protein associating with the ATG12-ATG5 conjugate during autophagosome formation. Altogether these studies clearly demonstrate that Cav-1 competitively interacts with the ATG12-ATG5 system to suppress the formation and function of the latter in lung epithelial cells, thereby providing new insights into the molecular mechanisms by which Cav-1 regulates autophagy and suggesting the important function of Cav-1 in certain lung diseases via regulation of autophagy homeostasis.caveolin-1; ATG12-ATG5; ATG16L; autophagy; lung diseases AUTOPHAGY IS A DYNAMIC PROCESS responsible for the turnover of cellular organelles and long-lived proteins. During this process, cytosolic proteins and organelles (e.g., mitochondria and endoplasmic reticulum) are engulfed into double-membranebound vesicles, autophagosomes. The outer membrane of the autophagosome subsequently fuses with lysosomes to form autolysosomes in which the engulfed components are degraded by lysosomal hydrolases, regenerating metabolic precursors that are recycled for macromolecular synthesis and ATP generation (20, 42). Autophagy is induced above basal levels in response to diverse stimuli including nutrient starvation, genotoxic agents, cytokines, and oxidative stress. This process provides an essential function in the maintenance of cellular homeostasis and adaptation to adverse environments (16,29,35).More than 30 autophagy-related genes and gene products critical in the regulation of autophagy, designated "ATG," have been identified heretofore in yeast and hi...

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Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation

Cited by 69 publications

References 44 publications

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity

Interaction of caveolin-1 with ATG12-ATG5 system suppresses autophagy in lung epithelial cells

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