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Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice

View Article: PubMed Central - PubMed

ABSTRACT

Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

No MeSH data available.


LPA1/3 inhibition retains circulating CCR2+ neutrophils and monocytes at low levels while increasing, Ly6Clow patrolling monocytes over time.(a) No difference was observed in the circulating neutrophil percentage between the two groups of animals. (b) CCR2+ expressing neutrophils were reduced after 4 weeks of LPA 1/3 antagonism. (c) Circulating monocytes showed a slight reduction upon 4 weeks of Ki16425 treatment (d) CCR2+ monocytes remained at lower levels in the course of LPA1/3 inhibition. (e) Non-inflammatory monocytes appeared significantly higher at 2 and 4 weeks of LPA1/3 inhibition. (f) The ratio of inflammatory/non-inflammatory monocytes was increased in the control group compared to the treated. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001).
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f4: LPA1/3 inhibition retains circulating CCR2+ neutrophils and monocytes at low levels while increasing, Ly6Clow patrolling monocytes over time.(a) No difference was observed in the circulating neutrophil percentage between the two groups of animals. (b) CCR2+ expressing neutrophils were reduced after 4 weeks of LPA 1/3 antagonism. (c) Circulating monocytes showed a slight reduction upon 4 weeks of Ki16425 treatment (d) CCR2+ monocytes remained at lower levels in the course of LPA1/3 inhibition. (e) Non-inflammatory monocytes appeared significantly higher at 2 and 4 weeks of LPA1/3 inhibition. (f) The ratio of inflammatory/non-inflammatory monocytes was increased in the control group compared to the treated. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001).

Mentions: Since the reduced CCL2 levels could induce lower inflammatory cell infiltration, and therefore lower the plaque size, it was particularly intriguing to focus on immune cells that respond to this chemokine via its specific receptor, CCR2. For that reason two additional groups of LDLr−/− mice were treated with either Ki16425 or vehicle-control for 6 weeks while on WTD. In the blood the overall percentage of circulating neutrophils, defined as Ly6G+ CD11b+/NK1.1− cells, was not affected by the treatment (Fig. 4a). However, the relative amount of circulating CCR2+ neutrophils was significantly increased over time in the control group (Fig. 4b, control: w0 compared to w2, P = 0.031; w0 compared to w4, P = 0.0001), but was found reduced in the treated animals after 4 weeks of LPA1/3 inhibition (w4: Ki16425 compared to control, P = 0.0060).


Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice
LPA1/3 inhibition retains circulating CCR2+ neutrophils and monocytes at low levels while increasing, Ly6Clow patrolling monocytes over time.(a) No difference was observed in the circulating neutrophil percentage between the two groups of animals. (b) CCR2+ expressing neutrophils were reduced after 4 weeks of LPA 1/3 antagonism. (c) Circulating monocytes showed a slight reduction upon 4 weeks of Ki16425 treatment (d) CCR2+ monocytes remained at lower levels in the course of LPA1/3 inhibition. (e) Non-inflammatory monocytes appeared significantly higher at 2 and 4 weeks of LPA1/3 inhibition. (f) The ratio of inflammatory/non-inflammatory monocytes was increased in the control group compared to the treated. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001).
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Related In: Results  -  Collection

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f4: LPA1/3 inhibition retains circulating CCR2+ neutrophils and monocytes at low levels while increasing, Ly6Clow patrolling monocytes over time.(a) No difference was observed in the circulating neutrophil percentage between the two groups of animals. (b) CCR2+ expressing neutrophils were reduced after 4 weeks of LPA 1/3 antagonism. (c) Circulating monocytes showed a slight reduction upon 4 weeks of Ki16425 treatment (d) CCR2+ monocytes remained at lower levels in the course of LPA1/3 inhibition. (e) Non-inflammatory monocytes appeared significantly higher at 2 and 4 weeks of LPA1/3 inhibition. (f) The ratio of inflammatory/non-inflammatory monocytes was increased in the control group compared to the treated. All values are calculated as mean ± SEM. (n = 12/grp, *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001).
Mentions: Since the reduced CCL2 levels could induce lower inflammatory cell infiltration, and therefore lower the plaque size, it was particularly intriguing to focus on immune cells that respond to this chemokine via its specific receptor, CCR2. For that reason two additional groups of LDLr−/− mice were treated with either Ki16425 or vehicle-control for 6 weeks while on WTD. In the blood the overall percentage of circulating neutrophils, defined as Ly6G+ CD11b+/NK1.1− cells, was not affected by the treatment (Fig. 4a). However, the relative amount of circulating CCR2+ neutrophils was significantly increased over time in the control group (Fig. 4b, control: w0 compared to w2, P = 0.031; w0 compared to w4, P = 0.0001), but was found reduced in the treated animals after 4 weeks of LPA1/3 inhibition (w4: Ki16425 compared to control, P = 0.0060).

View Article: PubMed Central - PubMed

ABSTRACT

Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

No MeSH data available.