Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

Linder, A. Elizabeth; McCluskey, Lynnette Phillips; Cole, Kenneth R.; Lanning, Katherine M.; Webb, R. Clinton

doi:10.1124/jpet.105.083634

Cited by 61 publications

(69 citation statements)

References 46 publications

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“…Some PDEs may also translocate from the cytoplasm to the nucleus in proliferating VSMCs (31). In contrast, our observation that MRP4 is localized in caveolin-enriched fractions indicates that MRP4 may exert tighter control over cAMP and cGMP neosynthesis (32,33). It remains to be seen whether MRP4 quenches cyclic nucleotide production, in contrast to PDEs, which may regulate more specific pools of cyclic nucleotides inside cells.…”

Section: Figurecontrasting

confidence: 49%

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation

Sassi¹,

Lipskaia²,

et al. 2008

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The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation. Introduction cAMP and cGMP are second messengers that relay external signals to downstream effector proteins. The most common targets are cAMP-dependent PKA and cGMP-dependent PKG, which regulate a large number of processes by phosphorylating target proteins. In addition to PKA, recent evidence has highlighted a major role for guanine-nucleotide exchange factors for Rap proteins (namely EPAC1 and EPAC2) (1) in mediating cAMP signaling. cAMP and cGMP also act by binding certain ion channels (2). Signaling events triggered by extracellular stimuli arise from an ingenious system of regulation that involves the production and elimination of intracellular cyclic nucleotides. Classically, cyclic nucleotide elimination has been attributed to hydrolysis mediated by cyclic nucleotide phosphodiesterases (PDEs). PDEs constitute a large superfamily of enzymes encoded by several genes with tissue-specific expression of a large number of splice variants (3). In several models, including VSMCs, PDEs have been shown to regulate the amplitude and duration of intracellular cyclic nucleotide signaling (4, 5). For instance, sildenafil, a selective PDE5 inhibi-

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Section: Figurecontrasting

confidence: 49%

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation

Sassi¹,

Lipskaia²,

et al. 2008

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“…When the plateau was reached, concentration-effect curves to the NO donors TERPY (1 nM-300 M) (de Lima et al, 2006) and SNP (0.1 nM-10 M) were constructed in the 2K and 2K-1C aortic rings. Methyl-␤-cyclodextrin (CD) (10 mM) (Linder et al, 2005), a caveolae disassembler, was added 60 min before phenylephrine to examine the effect of CD on the relaxation induced by the NO donors. Concentration-effect curves to both TERPY and SNP were constructed in aortic rings from 2K and 2K-1C rats, precontracted with phenylephrine in the presence or in the absence of CD.…”

Section: Vascular Reactivity Studiesmentioning

confidence: 99%

“…Previous studies have shown that cell exposure to sterol-binding agents such as methyl-␤-cyclodextrin removes cholesterol from the plasmalemma. This causes caveolae disassembly (Linder et al, 2005), whereas the general morphology of the tissue is preserved.…”

mentioning

confidence: 99%

Caveolae Dysfunction Contributes to Impaired Relaxation Induced by Nitric Oxide Donor in Aorta from Renal Hypertensive Rats

Rodrigues

Restini

Lunardi

et al. 2007

J Pharmacol Exp Ther

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Relaxation induced by nitric oxide (NO) donors is impaired in renal hypertensive two kidney-one clip (2K-1C) rat aortas. It has been proposed that caveolae are important in signal transduction and Ca 2ϩ homeostasis. Therefore, in the present study we investigate the integrity of caveolae in vascular smooth muscle cells (VSMCs), as well as their influence on the effects produced by NO released from both the new NO donor [Ru(NH.NHq) (terpy)NO ϩ ] 3ϩ (TERPY) and sodium nitroprusside (SNP) on 2K-1C rat aorta. The potency of both TERPY and SNP was lower in the 2K-1C aorta that in the normotensive aorta [two kidney (2K)], whereas the maximal relaxant effect (ME) was similar in both 2K-1C and 2K aortas. In the 2K aorta, methyl-␤-cyclodextrin (CD) reduced both the potency of TERPY and SNP, and their ME compared with the control, but it had no effect on the potency and ME of these NO donors in 2K-1C aortas. The decrease in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ) induced by TERPY was larger in 2K than in 2K-1C cells, and this effect was inhibited by CD in 2K cells only. Aortic VSMCs from 2K rats presented a larger number of caveolae than those from 2K-1C rats. Treatment with CD reduced the number of caveolae in both 2K and 2K-1C aortic VSMCs. Our results support the idea that caveolae play a critical role in the relaxant effect and in the decrease in [Ca 2ϩ

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“…Caveolin-1, a member of the protein caveolin family, is the major coat protein of caveolae (Anderson, 1998). Caveolae exist in most cell types and are particularly abundant in endothelial and smooth muscle cells (Ishizaka et al, 1998;Linder et al, 2005).…”

mentioning

confidence: 99%

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

Linder¹,

Thakali²,

Thompson³

et al. 2007

J Pharmacol Exp Ther

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Tachyphylaxis or desensitization is frequently observed following angiotensin II type I (AT 1 ) receptor activation by angiotensin II. One of the possible mechanisms contributing to receptor desensitization involves receptor internalization. In addition to clathrin-coated pits/vesicles, caveolae, small invaginations in the plasma membrane rich in cholesterol, may also be involved in receptor internalization. After activation, AT 1 receptor partially redistributes to lipid-enriched domains. We hypothesize that AT 1 receptor internalization via caveolae contributes to the tachyphylactic response observed to angiotensin II. Endothelium-denuded rat aortic rings were exposed to increasing concentrations of angiotensin II or phenylephrine, generating two cumulative concentration-effect curves (CCEC) with a 90-min interval separating each curve (CCEC-I and CCEC-II). CCEC-II was performed in the presence of either vehicle or methyl-␤-cyclodextrin (CD), a drug that depletes cholesterol from the membrane and disassembles caveolae. CCEC-II to angiotensin II, but not to phenylephrine, was blunted in aortic rings treated with vehicle. In the presence of CD, CCEC-II did not differ significantly from CCEC-I for both agonists. CCEC-I to angiotensin II was abolished when in the presence of the AT 1 receptor antagonist. The presence of AT 1 receptors at the aortic smooth muscle cells' membrane treated with angiotensin II was observed by immunofluorescence only in the presence of CD. In addition, caveolin-1 coimmunoprecipitated with AT 1 receptor after agonist stimulation, and this interaction was inhibited by CD. Our data suggest that caveolae are involved in the tachyphylactic contractile response induced by angiotensin II in rat aorta, and this effect is related to receptor internalization.

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Dynamic Association of Nitric Oxide Downstream Signaling Molecules with Endothelial Caveolin-1 in Rat Aorta

Cited by 61 publications

References 46 publications

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation

Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation

Caveolae Dysfunction Contributes to Impaired Relaxation Induced by Nitric Oxide Donor in Aorta from Renal Hypertensive Rats

Methyl-β-cyclodextrin Prevents Angiotensin II-Induced Tachyphylactic Contractile Responses in Rat Aorta

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