Short-term pravastatin mediates growth inhibition and apoptosis, independently of Ras, via the signaling proteins p27(Kip1) and PI3 kinase

Robert H Weiss, Al Ramirez, Adriane Joo

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3- hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T 1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 μM pravastatin before platelet- derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-β receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP- ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27(Kip1) are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27(Kip1), mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.

Original languageEnglish (US)
Pages (from-to)1880-1890
Number of pages11
JournalJournal of the American Society of Nephrology
Volume10
Issue number9
StatePublished - Sep 1999

Fingerprint

Cyclin-Dependent Kinase Inhibitor p27
Pravastatin
Phosphatidylinositol 3-Kinases
Apoptosis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Growth
Phosphatidylinositol 3-Kinase
Vascular Smooth Muscle
Smooth Muscle Myocytes
Phosphorylation
Hydroxymethylglutaryl CoA Reductases
Platelet-Derived Growth Factor Receptors
DNA
Extracellular Signal-Regulated MAP Kinases
Mitogens
Adenosine Diphosphate
Tyrosine
Intercellular Signaling Peptides and Proteins
Proteins
Cell Line

ASJC Scopus subject areas

  • Nephrology

Cite this

@article{52032232a6274652957d874f628f0733,
title = "Short-term pravastatin mediates growth inhibition and apoptosis, independently of Ras, via the signaling proteins p27(Kip1) and PI3 kinase",
abstract = "Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3- hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T 1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 μM pravastatin before platelet- derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-β receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP- ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27(Kip1) are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27(Kip1), mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.",
author = "Weiss, {Robert H} and Al Ramirez and Adriane Joo",
year = "1999",
month = "9",
language = "English (US)",
volume = "10",
pages = "1880--1890",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "9",

}

TY - JOUR

T1 - Short-term pravastatin mediates growth inhibition and apoptosis, independently of Ras, via the signaling proteins p27(Kip1) and PI3 kinase

AU - Weiss, Robert H

AU - Ramirez, Al

AU - Joo, Adriane

PY - 1999/9

Y1 - 1999/9

N2 - Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3- hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T 1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 μM pravastatin before platelet- derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-β receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP- ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27(Kip1) are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27(Kip1), mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.

AB - Growth factor-stimulated DNA synthesis in a variety of cell lines has been shown to be decreased after overnight (or longer) treatment with the 3- hydroxy-3-methylglutaryl CoA reductase inhibitors, the statins. Although this anti-mitogenic effect had been presumed to be the result of the impairment of Ras lipidation, a stable modification (T 1/2 approximately 20 h), this study provides new data demonstrating that brief (approximately 1 h) pretreatment of rat vascular smooth muscle cells with 100 μM pravastatin before platelet- derived growth factor-BB (PDGF-BB) stimulation results in attenuation of DNA synthesis through a Ras-independent mechanism. PDGF-BB-stimulated PDGF-β receptor tyrosine phosphorylation, Ras activity, and mitogen-activated protein/extracellular signal-regulated kinase activity are unaffected by from 10 min to 1 h of pravastatin incubation, while Raf activity is markedly increased after 1 h of pravastatin. Phosphatidylinositol-3 kinase activity and phosphorylation of its downstream effector Akt are decreased after 1 h pravastatin incubation. Rho is stabilized by pravastatin, and ADP- ribosylation of Rho by C3 exoenzyme decreases PDGF-stimulated phosphatidylinositol-3 kinase activity, mimicking the effect of pravastatin on this signaling protein. Levels of the cyclin-dependent kinase inhibitor p27(Kip1) are increased when cells were preincubated with pravastatin for 1 h and then exposed to PDGF, and apoptosis is induced by pravastatin incubation times as short as 1 to 4 h. Thus, short-term, high-dose pravastatin inhibits vascular smooth muscle cell growth and induces apoptosis independently of Ras, likely by means of the drug's effect on p27(Kip1), mediated by Rho and/or phosphatidylinositol-3 kinase. This work demonstrates for the first time that the statins may be therapeutically useful when applied for short periods of time such that potential toxicity of long-term statin use (such as chronic Ras inhibition) may be avoided, suggesting future therapeutic directions for statin research.

UR - http://www.scopus.com/inward/record.url?scp=0032803586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032803586&partnerID=8YFLogxK

M3 - Article

C2 - 10477139

AN - SCOPUS:0032803586

VL - 10

SP - 1880

EP - 1890

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 9

ER -