Mechanisms of Statin-mediated Inhibition of Small G-protein Function

Cordle, Andrew C.; Koenigsknecht-Talboo, Jessica; Wilkinson, Brandy; Limpert, Allison S.; Landreth, Gary E.

doi:10.1074/jbc.m505268200

Cited by 217 publications

(190 citation statements)

References 67 publications

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“…For instance, our laboratory and several others have recently unraveled the role of RhoA/ROCK in vascular endothelial growth factor (VEGF) signaling, an important mediator of microvascular complications of diabetes (34,35). We determined that VEGF-induced glo- by their inhibitory effects on RhoA/ROCK signaling (28,32,38). Indeed, we and others have previously shown that the inhibitory effects of statins on RhoA/ROCK signaling pathways may play an important role in the pleiotropic effects of statins (31,33,34).…”

Section: Discussionmentioning

confidence: 99%

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Kolavennu

Zeng²,

Peng³

et al. 2008

Diabetes

187

167

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OBJECTIVE-RhoA, a small GTPase protein, and its immediate downstream target, Rho kinase (ROCK), control a wide variety of signal transduction pathways. Recent studies have shown that fasudil, a selective ROCK inhibitor, may play a pivotal role in a number of pathological conditions, ranging from cardiovascular diseases to pulmonary hypertension and erectile dysfunction. Considerable evidence suggests that some of the beneficial effects of statins may also stem from their modulatory effects on RhoA/ROCK signaling. In the current study, we hypothesized that pharmacological blockade of the RhoA/ROCK pathway with either fasudil or simvastatin would ameliorate progression of diabetic nephropathy. RESULTS-The kidney cortices of untreated db/db mice displayed increased ROCK activity compared with db/m mice. The fasudil-treated mice exhibited a significant reduction in ROCK activity, albuminuria, glomerular collagen IV accumulation, and urinary collagen IV excretion compared with untreated db/db mice. Interestingly, blood glucose was unaffected by fasudil administration. Treatment with simvastatin significantly attenuated RhoA activation in the kidney cortices of db/db mice and resulted in a significant reduction of albuminuria and mesangial matrix expansion. RESEARCH DESIGN AND METHODS-InCONCLUSIONS-Based on these results, we propose that RhoA/ROCK blockade constitutes a novel approach to the treatment of diabetic nephropathy. Our data also suggest a critical role for RhoA/ROCK activation in the pathogenesis of diabetic nephropathy. Diabetes 57:714-723, 2008 T he Rho family of small GTPases are 20-to 40-kDa monomeric G proteins that regulate a number of cell functions, including cytoskeletal reorganization, cell motility, and gene expression (1). They cycle between two conformational states: an active GTPbound state and an inactive GDP-bound state (2). One of the best recognized members of the Rho GTPase family is RhoA. Rho kinase (ROCK), a downstream effector of RhoA, is a serine/threonine kinase of ϳ160 kDa that exists in two isoforms in mammals: ROCK1 and ROCK2 (3). ROCK is comprised of an amino-terminal kinase domain, followed by a coiled-coil region that contains the -binding domain. The carboxy-terminal consists of a plexstrinhomology domain, which contains an internal cysteinerich domain. ROCK1 and ROCK2 are highly homologous, sharing an identity of 65% in their overall amino acid sequences and 92% in their kinase domains.The RhoA/ROCK pathway has recently received considerable attention for its involvement in a wide variety of pathological states ranging from cardiovascular disease and pulmonary hypertension to Alzheimer's disease and glaucoma (4 -7). A growing body of evidence also suggests that the RhoA/ROCK pathway may have renomodulatory effects. Indeed, several recent studies have proposed that RhoA/ROCK may play an important role in renal fibrosis by enhancing signaling pathways involving transforming growth factor-␤, angiotensin II, and nuclear factor-B (8 -10). Furthermore, since the discovery of fasudi...

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Section: Discussionmentioning

confidence: 99%

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Kolavennu

Zeng²,

Peng³

et al. 2008

Diabetes

187

167

View full text Add to dashboard Cite

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“…A growing body of evidence also suggests that the essential role for protein prenylation is for optimal interaction of specific G-proteins, such as Rac1, with their regulatory proteins, such as Rho GDI (33,40,41). It is well established that GDI plays a regulatory role in membrane targeting of the active GTP-bound Rac1, as well as sequestration of the GDP-bound (inactive form) of Rac1 (4).…”

Section: Discussionmentioning

confidence: 99%

Dominant-Negative α-Subunit of Farnesyl- and Geranyltransferase Inhibits Glucose-Stimulated, but Not KCl-Stimulated, Insulin Secretion in INS 832/13 Cells

et al. 2007

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The majority of small G-proteins undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications increase their hydrophobicity, culminating in translocation of the modified proteins to their relevant membranous sites for interaction with their respective effectors. Previously, we reported glucose-dependent activation and membrane association of

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“…Secondary antimouse and anti-rabbit antibodies either peroxidasecoupled or 35 S-labeled were from GE Healthcare Life Sciences (Freiburg, Germany). ECL detection reagent was from Pierce; methyl-β-cyclodextrin (MβCD), Zaragozic acid A, mevalonate, and lovastatin were from Sigma-Aldrich (Germany).…”

Section: Methodsmentioning

confidence: 99%

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

Kojro

Füger

Prinzen

et al. 2010

JAD

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Abstract. Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-β protein precursor (AβPP) and are reported to stimulate the activity of α-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the α-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in α-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates α-secretase activity. Treatment of human neuroblastoma cells with 50 µM zaragozic acid resulted in a ∼3 fold increase of α-secretase activity and reduced cellular cholesterol by ∼30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 µM). Zaragozic acid-stimulated secretion of α-secretase cleaved soluble AβPP was dose dependent and saturable. Lovastatin-or zaragozic acid-stimulated increase of α-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the α-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AβPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for α-secretase activation.

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Mechanisms of Statin-mediated Inhibition of Small G-protein Function

Cited by 217 publications

References 67 publications

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Targeting of RhoA/ROCK Signaling Ameliorates Progression of Diabetic Nephropathy Independent of Glucose Control

Dominant-Negative α-Subunit of Farnesyl- and Geranyltransferase Inhibits Glucose-Stimulated, but Not KCl-Stimulated, Insulin Secretion in INS 832/13 Cells

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

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