A rapid, PPAR-γ-dependent effect of pioglitazone on the phosphorylation of MYPT

Atkins, Kevin B.; Irey, Brittany; Nan, Xuemei; Brosius, Frank C.

doi:10.1152/ajpcell.00343.2008

Cited by 29 publications

(13 citation statements)

References 29 publications

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“…In primary rat VSMCs, PIO promotes the activation of myosin light chain phosphatase, thus reducing phosphorylation of myosin light chain (21). Similarly, Wakino et al (22) demonstrated that PIO and troglitazone treatment suppresses Ang II-stimulated Rho kinase activity in vitro.…”

Section: Vascular Smooth Muscle Ppar␥mentioning

confidence: 93%

Does Peroxisome Proliferator-activated Receptor-γ (PPARγ) Protect from Hypertension Directly through Effects in the Vasculature?

Ketsawatsomkron

Pelham

Groh

et al. 2010

Journal of Biological Chemistry

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) is a ligand-activated transcription factor of the nuclear hormone receptor superfamily. Increasing evidence suggests that PPAR␥ is involved in the regulation of vascular function and blood pressure in addition to its well recognized role in metabolism. Thiazolidinediones, PPAR␥ agonists, lower blood pressure and have protective vascular effects through largely unknown mechanisms. In contrast, loss-of-function dominant-negative mutations in human PPAR␥ cause insulin resistance and severe early onset hypertension. Recent studies using genetically manipulated mouse models have begun to specifically address the importance of PPAR␥ in the vasculature. In this minireview, evidence for a protective role of PPAR␥ in the endothelium and vascular smooth muscle, derived largely from studies of genetically manipulated mice, will be discussed.

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Section: Vascular Smooth Muscle Ppar␥mentioning

confidence: 93%

Does Peroxisome Proliferator-activated Receptor-γ (PPARγ) Protect from Hypertension Directly through Effects in the Vasculature?

Ketsawatsomkron

Pelham

Groh

et al. 2010

Journal of Biological Chemistry

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“…Stable HEK-293 cell lines expressing human RGS2 or RGS4 tagged with the 4-kDa ProLabel tag were described previously (Sjogren et al, 2012). Primary rat vascular smooth muscle cells (VSMC) were prepared as previously described (Atkins et al, 2009). Cells were used from passages 3 to 8.…”

Section: Mgmentioning

confidence: 99%

“…We used primary rat VSMC that have endogenous expression of RGS2 protein (Atkins et al, 2009;Sjogren et al, 2012). As demonstrated in Fig.…”

Section: Pkc Activation Increases Rgs2 Protein Levelsmentioning

confidence: 99%

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

Raveh

Schultz

Aschermann

et al. 2014

Molecular Pharmacology

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Biochemical high-throughput screening is widely used in drug discovery, using a variety of small molecule libraries. However, broader screening strategies may be more beneficial to identify novel biologic mechanisms. In the current study we used a b-galactosidase complementation method to screen a selection of microbial-derived pre-fractionated natural product extracts for those that increase regulator of G protein signaling 2 (RGS2) protein levels. RGS2 is a member of a large family of proteins that all regulate signaling through G protein-coupled receptors (GPCRs) by accelerating GTPase activity on active Ga as well as through other mechanisms. RGS22/2 mice are hypertensive, show increased anxiety, and are prone to heart failure. RGS2 has a very short protein halflife due to rapid proteasomal degradation, and we propose that enhancement of RGS2 protein levels could be a beneficial therapeutic strategy. Bioassay-guided fractionation of one of the hit strains yielded a pure compound, Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time-and concentrationdependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate as well as activation of the Gqcoupled muscarinic M 3 receptor. The effect on RGS2 protein levels was blocked by the nonselective PKC inhibitor Gö6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione), the PKCb-selective inhibitor Ruboxastaurin, as well as small interfering RNA-mediated knockdown of PKCb. Indolactam V-mediated increases in RGS2 protein levels also had functional effects on GPCR signaling. This study provides important proof-of-concept for our screening strategy and could define a negative feedback mechanism in Gq/Phospholipase C signaling through RGS2 protein upregulation.

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“…All animal studies were reviewed and approved by the University of Michigan Committee on the Use and Care of Animals. Primary rat aortic vascular smooth muscle cells (VSMCs) were prepared as described previously (Atkins et al, 2009). Cells were used in passages 3 to 8.…”

Section: Materials N-(benzyloxycarbonyl)leucinylleucinylleucinalmentioning

confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

Sjögren

Parra

Heath

et al. 2012

Molecular Pharmacology

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Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

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A rapid, PPAR-γ-dependent effect of pioglitazone on the phosphorylation of MYPT

Cited by 29 publications

References 29 publications

Does Peroxisome Proliferator-activated Receptor-γ (PPARγ) Protect from Hypertension Directly through Effects in the Vasculature?

Does Peroxisome Proliferator-activated Receptor-γ (PPARγ) Protect from Hypertension Directly through Effects in the Vasculature?

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

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