HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection

BMC Cardiovascular Disorders

Colin Green²  Joannis E Vamvakopoulos¹ 

[1] Current address: Rational Drug Design Program, Biomedicum Helsinki, Helsinki, Finland;Northwick Park Institute for Medical Research, Harrow, UK

关键词: leukocytes;    drugs;    cholesterol;    arteriosclerosis;    apoptosis;   

Others  :  1088615
DOI  :  10.1186/1471-2261-3-6

 received in 2003-02-26, accepted in 2003-07-19,  发布年份 2003

【 摘 要 】

Background

Statins effectively lower blood cholesterol and the risk of cardiovascular death. Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds. Since macrophages participate in several vascular pathologies, we examined the effect of statin treatment on the survival and differentiation of primary human monocytes.

Methods

Peripheral blood mononuclear cells (PBMCs) from healthy individuals were cultured in the presence or absence of mevastatin. Apoptosis was monitored by annexin V / PI staining and flow cytometry. In parallel experiments, cultures were stimulated with LPS in the presence or absence of mevastatin and the release of IL-1β and IL-1Ra was measured by ELISA.

Results

Among PBMCs, mevastatin-treated monocytes were particularly susceptible to apoptosis, which occurred at doses >1 microM and was already maximal at 5 microM. However, even at the highest mevastatin dose used (10 microM), apoptosis occurred only after 24 h of culture, possibly reflecting a requirement for cell commitment to differentiation. After 72 h of treatment the vast majority (>50%) of monocytes were undergoing apoptosis. Stimulation with LPS revealed that mevastatin-treated monocytes retained the high IL-1β output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1β and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.

Conclusions

Our findings indicate that statins arrest the functional differentiation of monocytes into macrophages and steer these cells into apoptosis, suggesting a novel mechanism for the vasculoprotective properties of HMG-CoA reductase inhibitors.

【 授权许可】

   
2003 Vamvakopoulos and Green; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

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