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

Vamvakopoulos JE, Green C - BMC Cardiovasc Disord (2003)

Bottom Line: Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds.Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, University of Cambridge, Cambridge, UK. joannis@scientist.com

ABSTRACT

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-1beta 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-1beta output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta 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.

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Related in: MedlinePlus

Mevastatin arrests the functional maturation of cultured human peripheral blood monocytes. LPS was added to PBMC cultures either at the onset (undifferentiated control), or after 24 h, of cell culture and supernatants were harvested 24 h later in each case. Pre-treatment with γIFN was only applicable to differentiating cells. Mevastatin treatment preserved monocyte responsiveness to LPS in terms of IL-1β release (A) but suppressed IL-1Ra release (B). *, p < 0.05; **, p < 0.01 (brackets indicate groups being compared).
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Figure 3: Mevastatin arrests the functional maturation of cultured human peripheral blood monocytes. LPS was added to PBMC cultures either at the onset (undifferentiated control), or after 24 h, of cell culture and supernatants were harvested 24 h later in each case. Pre-treatment with γIFN was only applicable to differentiating cells. Mevastatin treatment preserved monocyte responsiveness to LPS in terms of IL-1β release (A) but suppressed IL-1Ra release (B). *, p < 0.05; **, p < 0.01 (brackets indicate groups being compared).

Mentions: Interleukin-1β release after LPS stimulation is suppressed early during monocyte-to-macrophage differentiation in vitro and in vivo. Continuous mevastatin treatment of non-stimulated human PBMCs for 48 h did not affect constitutive IL-1β output (47.7 +/- 13.6 vs 45.1 +/- 9.0 pg/mL in vehicle-treated cultures). However, when LPS was added at 24 h mevastatin-treated cells released approximately 40-fold more IL-1β compared to vehicle-treated cells (15,559.1 +/- 5,518 vs 389.2 +/- 163 pg/mL; p = 0.05), a level comparable to that obtained with freshly harvested, undifferentiated monocytes (figure 3A).


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

Vamvakopoulos JE, Green C - BMC Cardiovasc Disord (2003)

Mevastatin arrests the functional maturation of cultured human peripheral blood monocytes. LPS was added to PBMC cultures either at the onset (undifferentiated control), or after 24 h, of cell culture and supernatants were harvested 24 h later in each case. Pre-treatment with γIFN was only applicable to differentiating cells. Mevastatin treatment preserved monocyte responsiveness to LPS in terms of IL-1β release (A) but suppressed IL-1Ra release (B). *, p < 0.05; **, p < 0.01 (brackets indicate groups being compared).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC183828&req=5

Figure 3: Mevastatin arrests the functional maturation of cultured human peripheral blood monocytes. LPS was added to PBMC cultures either at the onset (undifferentiated control), or after 24 h, of cell culture and supernatants were harvested 24 h later in each case. Pre-treatment with γIFN was only applicable to differentiating cells. Mevastatin treatment preserved monocyte responsiveness to LPS in terms of IL-1β release (A) but suppressed IL-1Ra release (B). *, p < 0.05; **, p < 0.01 (brackets indicate groups being compared).
Mentions: Interleukin-1β release after LPS stimulation is suppressed early during monocyte-to-macrophage differentiation in vitro and in vivo. Continuous mevastatin treatment of non-stimulated human PBMCs for 48 h did not affect constitutive IL-1β output (47.7 +/- 13.6 vs 45.1 +/- 9.0 pg/mL in vehicle-treated cultures). However, when LPS was added at 24 h mevastatin-treated cells released approximately 40-fold more IL-1β compared to vehicle-treated cells (15,559.1 +/- 5,518 vs 389.2 +/- 163 pg/mL; p = 0.05), a level comparable to that obtained with freshly harvested, undifferentiated monocytes (figure 3A).

Bottom Line: Immunomodulatory actions, independent of their lipid-lowering effect, have also been ascribed to these compounds.Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta and IL-1Ra release in response to LPS, suggesting a rate-limiting role for HMG-CoA reductase in monocyte differentiation.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Surgery, University of Cambridge, Cambridge, UK. joannis@scientist.com

ABSTRACT

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-1beta 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-1beta output characteristic of undifferentiated cells; conversely, IL-1Ra release was inhibited. Concurrent treatment with mevalonolactone prevented the induction of apoptosis and suppressed both IL-1beta 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.

Show MeSH
Related in: MedlinePlus