Localization of Adenylyl Cyclase Isoforms and G Protein-Coupled Receptors in Vascular Smooth Muscle Cells: Expression in Caveolin-Rich and Noncaveolin Domains

Ostrom, Rennolds S.; Liu, Xiaoqiu; Head, Brian P.; Gregorian, Caroline; Seasholtz, Tammy M.; Insel, Paul A.

doi:10.1124/mol.62.5.983

Cited by 132 publications

(112 citation statements)

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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: Figurementioning

confidence: 63%

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: Figurementioning

confidence: 63%

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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“…Indeed, recent studies have provided the rationale for such discrepant effects of the two cGMP-generating pathways (28,29). First, it has been proposed that localization of GC enzymes within specialized structures (e.g., caveoli, vesicles, or endoplasmic reticulum) acts as a barrier to limit the spread of cGMP, similar to mechanisms suggested for cAMP (30). Second, different PDE isoforms might be involved in preventing the diffusion of cGMP.…”

Section: Discussionmentioning

confidence: 99%

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Baliga¹,

Zhao²,

Madhani³

et al. 2008

Am J Respir Crit Care Med

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Rationale: Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity. Objectives: We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways. Methods: Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH). Measurements and Main Results: Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure.Conclusions: These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.Keywords: guanylyl cyclase; cyclic GMP; nitric oxide; natriuretic peptides; neutral endopeptidase Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary arterial blood pressure, vascular remodeling of the pulmonary small arteries, right ventricular hypertrophy, and ultimately right ventricular failure (1, 2). Whether idiopathic PAH, familial PAH, or PAH associated with other diseases (e.g., congenital heart disease, HIV infection), the disease leads to premature death, in large part due to the paucity of satisfactory treatments, particularly vasodilators that selectively oppose the excessive vasoconstriction observed in the pulmonary vasculature, and agents able to reverse vascular wall remodeling. This therapeutic insufficiency is also a consequence of uncertainty regarding disease etiology. Current treatment options include prostacyclin analogs (3, 4) endothelin receptor antagonists (5, 6), and phosphodiesterase 5 (PDE5) inhibitors (i.e., sildenafil) (7), but despite these advances, 2-year mort...

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“…The cyclic guanosine monophosphate (cGMP)-phosphodiesterase involved in the visual signal transduction system has been shown to be recruited by DRMs following stimulation of rod outer-segment membranes with light and guanosine triphosphate gamma thio (GTP ␥ S) (81). Several different forms of adenylate cyclase, including types III, IV, V, and VI, have been found to be localized to lipid rafts (82,84,95,(98)(99)(100). Endogenous adenylate cyclase appears to consistently concentrate in lipid rafts, while overexpressed adenylate cyclase distributes to a variable degree between rafts and bulk plasma membranes, depending on the cell type examined (82,84,100).…”

Section: Lipid Rafts In G Protein-coupled Receptor Systemsmentioning

confidence: 99%

Lipid rafts: bringing order to chaos

Pike

2003

Journal of Lipid Research

1,036

473

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For 30 years, the fluid mosaic model of Singer and Nicolson (1) has provided the foundation for our understanding of the structure of cellular membranes. In this model, membrane proteins are viewed as icebergs floating in a sea of lipids. However, work over the last decade has provided evidence that the plasma membrane is not a random ocean of lipids. Rather, there is structure within this sea of lipids that in turn imposes organization on the distribution of proteins in the bilayer. The lipid "structures" within the membrane ocean are called lipid rafts.Lipid rafts are localized regions of elevated cholesterol and glycosphingolipid content within cell membranes (see Fig.

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Localization of Adenylyl Cyclase Isoforms and G Protein-Coupled Receptors in Vascular Smooth Muscle Cells: Expression in Caveolin-Rich and Noncaveolin Domains

Cited by 132 publications

References 48 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

Synergy between Natriuretic Peptides and Phosphodiesterase 5 Inhibitors Ameliorates Pulmonary Arterial Hypertension

Lipid rafts: bringing order to chaos

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