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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-treated differentiating monocytes are particularly susceptible to apoptosis. After 24 h of statin treatment monocytes still constituted a single, viable cell population (panel A, black arrow). By 48 h this viable monocytic population had decreased in size and a second population of smaller, annexin V-positive cells had appeared (B). By 72 h the majority of monocytes were undergoing apoptosis (C). Conversely, peripheral blood lymphocytes (white arrow) remained largely viable throughout the observation period. Results shown here are representative of 18 experiments (three per individual).
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Figure 1: Mevastatin-treated differentiating monocytes are particularly susceptible to apoptosis. After 24 h of statin treatment monocytes still constituted a single, viable cell population (panel A, black arrow). By 48 h this viable monocytic population had decreased in size and a second population of smaller, annexin V-positive cells had appeared (B). By 72 h the majority of monocytes were undergoing apoptosis (C). Conversely, peripheral blood lymphocytes (white arrow) remained largely viable throughout the observation period. Results shown here are representative of 18 experiments (three per individual).

Mentions: Prolonged mevastatin treatment was associated with massive apoptosis of cultured human peripheral blood monocytes, but not lymphocytes (figure 1). Incubation with mevastatin for 24 h did not compromise monocyte viability when compared to untreated or vehicle-treated cell cultures. However, a 48-h treatment with mevastatin resulted in the appearance of a large apoptotic monocyte population, as defined by light scatter criteria (granular cells of diminishing size) and annexin V-positive staining. At this time-point, 27.5 +/-1.8% of mevastatin-treated monocytes were undergoing apoptosis compared with 8.8 +/-1.6% of vehicle-treated monocytes (p = 0.001; figure 2).


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-treated differentiating monocytes are particularly susceptible to apoptosis. After 24 h of statin treatment monocytes still constituted a single, viable cell population (panel A, black arrow). By 48 h this viable monocytic population had decreased in size and a second population of smaller, annexin V-positive cells had appeared (B). By 72 h the majority of monocytes were undergoing apoptosis (C). Conversely, peripheral blood lymphocytes (white arrow) remained largely viable throughout the observation period. Results shown here are representative of 18 experiments (three per individual).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Mevastatin-treated differentiating monocytes are particularly susceptible to apoptosis. After 24 h of statin treatment monocytes still constituted a single, viable cell population (panel A, black arrow). By 48 h this viable monocytic population had decreased in size and a second population of smaller, annexin V-positive cells had appeared (B). By 72 h the majority of monocytes were undergoing apoptosis (C). Conversely, peripheral blood lymphocytes (white arrow) remained largely viable throughout the observation period. Results shown here are representative of 18 experiments (three per individual).
Mentions: Prolonged mevastatin treatment was associated with massive apoptosis of cultured human peripheral blood monocytes, but not lymphocytes (figure 1). Incubation with mevastatin for 24 h did not compromise monocyte viability when compared to untreated or vehicle-treated cell cultures. However, a 48-h treatment with mevastatin resulted in the appearance of a large apoptotic monocyte population, as defined by light scatter criteria (granular cells of diminishing size) and annexin V-positive staining. At this time-point, 27.5 +/-1.8% of mevastatin-treated monocytes were undergoing apoptosis compared with 8.8 +/-1.6% of vehicle-treated monocytes (p = 0.001; figure 2).

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