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EXPERIMENTAL STUDY

HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins

Zhihong Yang, MD^* , Toshiyoki Kozai, MD^* , Bernd van de Loo, MD^* , Hema Viswambharan, MSc^* , Mario Lachat, MD, Marko I. Turina, MD, Tadeusz Malinski, PhD and Thomas F. Lüscher, MD, FRCP, FACC^*

^* Department of Cardiovascular Research, Institute of Physiology, University Zürich-Irchel, Zürich, Switzerland
Department of Cardiology, University Hospital, Zürich, Switzerland
Clinic for Cardiovascular Surgery, University Hospital, Zürich, Switzerland
Department of Chemistry, Institut of Biotechnology, Oakland University, Rochester, Michigan, USA

Manuscript received May 10, 1999; revised manuscript received April 20, 2000, accepted June 26, 2000.

Reprint requests and correspondence: Dr. Thomas F. Lüscher, Cardiovascular Center, Cardiology, University Hospital, CH-8091 Zürich/Switzerland

OBJECTIVES

This study examined effects of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor cerivastatin on human saphenous vein (SV), endothelial cells (EC) and smooth muscle cells (SMC).

BACKGROUND

Venous bypass graft failure involves EC dysfunction and SMC proliferation. Substances that improve EC function and inhibit SMC proliferation would be of clinical relevance.

METHODS

Both EC and SMC were isolated from SV. Endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production were analyzed by immunoblotting and porphyrinic microsensor. The SMC proliferation was assayed by ³H-thymidine incorporation. Protein kinases and cell cycle regulators were analyzed by immunoblotting.

RESULTS

Cerivastatin (10^–9 to 10^–6 mol/liter) enhanced eNOS protein expression and NO release (about two-fold) in EC in response to Ca²⁺ ionophore (10^–6 mol/liter). This was fully abrogated by the HMG-CoA product mevanolate (2 x 10^–4 mol/liter). In SMC, platelet-derived growth factor (5 ng/ml) enhanced ³H-thymidine incorporation (298 ± 23%, n = 4), activated cyclin-dependent kinase (Cdk2), phosphorylated Rb and down-regulated p27^Kip1 (but not p21^Cip1). Cerivastatin reduced the ³H-thymidine incorporation (164 ± 11%, p < 0.01), inhibited Cdk2 activation and Rb phosphorylation, but did not prevent p27^Kip1 down-regulation, nor p42^mapk and p70^S6K activation. Mevalonate abrogated the effects of cerivastatin on Cdk2 and Rb but only partially rescued the ³H-thymidine incorporation (from 164 ± 11% to 211 ± 13%, n = 4, p < 0.01).

CONCLUSIONS

In humans, SVEC inhibition of HMG-CoA/mevalonate pathway contributes to the enhanced eNOS expression and NO release by cerivastatin, whereas in SMC, inhibition of this pathway only partially explains cerivastatin-induced cell growth arrest. Inhibition of mechanisms other than p42^mapk and p70^S6K or Cdk2 are also involved. These effects of cerivastatin could be important in treating venous bypass graft disease.

Abbreviations and Acronyms   Cdks = cyclin-dependent kinases   EC = endothelial cell(s)   eNOS = endothelial nitric oxide synthase   FCS = fetal calf serum   HMG-CoA = 3-hydroxy-3-methylglutaryl CoA   NO = nitric oxide   PBS = phosphate-buffered saline   PDGF = platelet-derived growth factor   SMC = smooth muscle cell(s)   SV = saphenous vein

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