Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation.
BACKGROUND
The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs).


RESULTS
Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg x kg(-1) x d(-1) and with fluvastatin at a dose of 1 mg x kg(-1) x d(-1), which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (approximately 5 micromol/L) for 24 hours significantly inhibited Ang II (1 micromol/L)-mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II-mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor-mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo.


CONCLUSIONS
These results suggest that the cholesterol-independent inhibition of AT1 receptor-mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.
Horiuchi
Masatsugu
M
Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan. horiuchi@m.ehime-u.ac.jp
Cui
Tai-Xing
TX
Li
Zhen
Z
Li
Jian-Mei
JM
Nakagami
Hironori
H
Iwai
Masaru
M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use*; D000077340:Fluvastatin; D016762:Genes, fos; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D044140:Receptor, Angiotensin, Type 1; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D004268:DNA-Binding Proteins; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000077340:Fluvastatin; D000068756:Valsartan; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D014633:Valine