Caveolae and Caveolin-1: Novel Potential Targets for the Treatment of Cardiovascular Disease

Frank, Philippe G.; Hassan, Ghada S.; Rodríguez-Feo, Juan A.; Lisanti, Michael P.

doi:10.2174/138161207780831202

Cited by 49 publications

(32 citation statements)

References 112 publications

(156 reference statements)

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“…A similar role for caveolin-1 in activation of Rac1, increased ROS production, and vascular hypertrophy after angiotensin II type 1 receptor activation has been suggested in vascular smooth muscle cells (17). Although both epithelial and endothelial cells express caveolin-1 (44,45), there is substantial evidence that lack of endothelial caveolin-1 plays a major role in the pathophysiology observed in caveolin-1 knock-out mice (46,47). Therefore, it is reasonable to speculate that the pulmonary effects we observe with hyperoxia treatment of mice are through a preferential endothelial-dependent, rather than epithelial-dependent, mechanism (46,47).…”

Section: And P47mentioning

confidence: 83%

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Singleton

Pendyala

Горшкова

et al. 2009

Journal of Biological Chemistry

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Reactive oxygen species (ROS) generation, particularly by the endothelial NADPH oxidase family of proteins, plays a major role in the pathophysiology associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilatorassociated lung injury. We examined potential regulators of ROS production and discovered that hyperoxia treatment of human pulmonary artery endothelial cells induced recruitment of the vesicular regulator, dynamin 2, the non-receptor tyrosine kinase, c-Abl, and the NADPH oxidase subunit, p47 phox , to caveolin-enriched microdomains (CEMs). Silencing caveolin-1 (which blocks CEM formation) and/or c-Abl expression with small interference RNA inhibited hyperoxia-mediated tyrosine phosphorylation and association of dynamin 2 with p47 phox and ROS production. In addition, treatment of human pulmonary artery endothelial cells with dynamin 2 small interfering RNA or the dynamin GTPase inhibitor, Dynasore, attenuated hyperoxia-mediated ROS production and p47 phox recruitment to CEMs. Using purified recombinant proteins, we observed that c-Abl tyrosine-phosphorylated dynamin 2, and this phosphorylation increased p47 phox /dynamin 2 association (change in the dissociation constant (K d ) from 85.8 to 6.9 nM). Furthermore, exposure of mice to hyperoxia increased ROS production, c-Abl activation, dynamin 2 association with p47 phox , and pulmonary leak, events that were attenuated in the caveolin-1 knock-out mouse confirming a role for CEMs in ROS generation. These results suggest that hyperoxia induces c-Abl-mediated dynamin 2 phosphorylation required for recruitment of p47 phox to CEMs and subsequent ROS production in lung endothelium.Vascular endothelial cell (EC) 2 barrier integrity is critical to normal vessel homeostasis with defects in the EC barrier contributing to inflammation, tumor angiogenesis, atherosclerosis, and acute lung injury (1). The generation of reactive oxygen species (ROS) in the vasculature plays a major role in EC activation and barrier function (2). Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS, and accumulation of ROS is associated with lung inflammation, ischemiareperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury (3). Activation of phagocytic NADPH oxidase requires the assembly of the cytosolic p47 phox , p67 phox , p40 phox , and Rac2 with membrane-associated cytochrome b 558 reductase, which consists of p22 phox and Nox2 (gp91 phox ). Vascular cells express similar subcomponents to phagocytic NADPH oxidase subunits, including Rac1, p47 phox , and Nox2 (2, 3). We have recently demonstrated that exposure of human pulmonary artery endothelial cells (HPAECs) to hyperoxia (95% O 2 ) increases the ROS production that is dependent on NADPH oxidase activation and independent of the mitochondrial electron transport or xanthine/xanthine oxidase systems (4).Regulation of NADPH oxidase activation in phagocytes requires serine phosphorylation of t...

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Section: And P47mentioning

confidence: 83%

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Singleton

Pendyala

Горшкова

et al. 2009

Journal of Biological Chemistry

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“…That these biochemical specializations of the raft/caveolar membrane are functionally important has now been shown in several smooth muscles by disrupting caveolae, usually by extracting cholesterol [rat uterus (648) and ureter (26), human myometrium (798), blood vessels (155), and bladder (273)]. A link with obesity, through elevated cholesterol and other smooth muscle pathologies, has recently been demonstrated (186,797).…”

Section: Caveolaementioning

confidence: 99%

Sarcoplasmic Reticulum Function in Smooth Muscle

Wray

Burdyga

2010

Physiological Reviews

154

134

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The sarcoplasmic reticulum (SR) of smooth muscles presents many intriguing facets and questions concerning its roles, especially as these change with development, disease, and modulation of physiological activity. The SR's function was originally perceived to be synthetic and then that of a Ca store for the contractile proteins, acting as a Ca amplification mechanism as it does in striated muscles. Gradually, as investigators have struggled to find a convincing role for Ca-induced Ca release in many smooth muscles, a role in controlling excitability has emerged. This is the Ca spark/spontaneous transient outward current coupling mechanism which reduces excitability and limits contraction. Release of SR Ca occurs in response to inositol 1,4,5-trisphosphate, Ca, and nicotinic acid adenine dinucleotide phosphate, and depletion of SR Ca can initiate Ca entry, the mechanism of which is being investigated but seems to involve Stim and Orai as found in nonexcitable cells. The contribution of the elemental Ca signals from the SR, sparks and puffs, to global Ca signals, i.e., Ca waves and oscillations, is becoming clearer but is far from established. The dynamics of SR Ca release and uptake mechanisms are reviewed along with the control of luminal Ca. We review the growing list of the SR's functions that still includes Ca storage, contraction, and relaxation but has been expanded to encompass Ca homeostasis, generating local and global Ca signals, and contributing to cellular microdomains and signaling in other organelles, including mitochondria, lysosomes, and the nucleus. For an integrated approach, a review of aspects of the SR in health and disease and during development and aging are also included. While the sheer versatility of smooth muscle makes it foolish to have a “one model fits all” approach to this subject, we have tried to synthesize conclusions wherever possible.

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“…These are flask-shaped membrane invaginations characterized by the presence of the scaffolding protein caveolin. 5 Whereas the presence of α1-AR in caveolae has been reported, 6 the localization of the K V 4.2 and K V 4.3 proteins, molecular correlates of the I to channel, is controversial.…”

Section: Introductionmentioning

confidence: 99%

α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K_V4 channels

Alday¹,

Urrutia²,

Gallego³

et al. 2010

Channels

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Caveolae and Caveolin-1: Novel Potential Targets for the Treatment of Cardiovascular Disease

Cited by 49 publications

References 112 publications

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Sarcoplasmic Reticulum Function in Smooth Muscle

α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K_V4 channels

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Caveolae and Caveolin-1: Novel Potential Targets for the Treatment of Cardiovascular Disease

Cited by 49 publications

References 112 publications

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Dynamin 2 and c-Abl Are Novel Regulators of Hyperoxia-mediated NADPH Oxidase Activation and Reactive Oxygen Species Production in Caveolin-enriched Microdomains of the Endothelium

Sarcoplasmic Reticulum Function in Smooth Muscle

α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac KV4 channels

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α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K_V4 channels