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EFFECT OF LOVASTATIN AND FLUOROMEVALONATE ON PHOSPHATIDYLINOSITOL 3‐KINASE ACTIVITY STIMULATED WITH PDGF
Author(s) -
Iwama A.,
Sawamura M.,
Nara Y.,
Yamori Y.
Publication year - 1995
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.1995.tb02935.x
Subject(s) - phosphatidylinositol , lovastatin , platelet derived growth factor receptor , endocrinology , chemistry , mevalonic acid , medicine , growth factor , biochemistry , kinase , enzyme , biology , cholesterol , receptor , reductase
Summary 1. Phosphatidylinositol 3‐kinase (PI3K) appears to have a crucial role in cellular proliferation induced by platelet‐derived growth factor (PDGF). However, the mode of activation of the enzyme has been unclear so far. In the present study, we investigated the effects of a cholesterol lowering drug on [ 3 H]‐thymidine ([ 3 H]‐TdR) incorporation and PI3K activity in cultured vascular smooth muscle cells (VSMC) stimulated with PDGF. 2. PDGF stimulated both [ 3 H]‐TdR incorporation and PI3K activity immunoprecipitated with antiphosphotyrosine antibody in a dose dependent manner (EDSO was 4 ng/mL for [ 3 H]‐TdR uptake and 3 ng/mL for PI3K activity). Lovastatin inhibited serum‐stimulated [ 3 H]‐TdR incorporation dose dependently. PI3K activity induced by PDGF was also inhibited in a dose dependent manner; however, its activity was 61% at 10 ‐6 mol/L, 72% at 10 ‐5 mol/L and 8% at 10 ‐4 mol/L of the control value. 3. These inhibitory effects of lovastatin were completely abolished by adding 1 mmol/L mevalonic acid (MVA), suggesting that MVA metabolites had some important role on the PI3K activation and cellular proliferation. 4. Fluoromevalonate (Fmev), a competitive inhibitor of mevalonate diphosphate (MVA‐PP) decarboxylase, inhibited [ 3 H]‐TdR incorporation at concentrations more than 10 ‐6 mol/L. Moreover, marked inhibitory effect was observed at concentrations of 10 ‐7 and 10 ‐8 mol/L (76% of control). PI3K activity was also reduced by 10 ‐3 mol/L Fmev (0.2% of control). However, in contrast to [ 3 H]‐TdR uptake, there was no inhibitory effect detected at concentrations up to 10 ‐4 mol/L. 5. These results suggest that PDGF‐stimulated PI3K activity as well as cellular proliferation was modified by protein isoprenylation.