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

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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.


Total CD3+ T-cell numbers in the aortic root show no difference between the control and Ki16425-treated groups.CD3+ cells in the aortic root of the hearts were determined upon manual quantification. No difference was observed in the CD3+ expressing cells of the aortic root upon LPA1/3 inhibition. All values (n = 12/grp) are depicted as mean ± SEM.
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f6: Total CD3+ T-cell numbers in the aortic root show no difference between the control and Ki16425-treated groups.CD3+ cells in the aortic root of the hearts were determined upon manual quantification. No difference was observed in the CD3+ expressing cells of the aortic root upon LPA1/3 inhibition. All values (n = 12/grp) are depicted as mean ± SEM.

Mentions: Considering that the systemic differences in the CD4+ T-cells upon LPA1/3 blockade may directly influence the T-cell content inside the atherosclerotic plaque, a CD3+ immunohistochemical staining was performed in the aortic root. However, no significant differences were observed upon manual quantification of the CD3+ cells in the three-valve area of both groups (Fig. 6, P = 0.43).


Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice
Total CD3+ T-cell numbers in the aortic root show no difference between the control and Ki16425-treated groups.CD3+ cells in the aortic root of the hearts were determined upon manual quantification. No difference was observed in the CD3+ expressing cells of the aortic root upon LPA1/3 inhibition. All values (n = 12/grp) are depicted as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121611&req=5

f6: Total CD3+ T-cell numbers in the aortic root show no difference between the control and Ki16425-treated groups.CD3+ cells in the aortic root of the hearts were determined upon manual quantification. No difference was observed in the CD3+ expressing cells of the aortic root upon LPA1/3 inhibition. All values (n = 12/grp) are depicted as mean ± SEM.
Mentions: Considering that the systemic differences in the CD4+ T-cells upon LPA1/3 blockade may directly influence the T-cell content inside the atherosclerotic plaque, a CD3+ immunohistochemical staining was performed in the aortic root. However, no significant differences were observed upon manual quantification of the CD3+ cells in the three-valve area of both groups (Fig. 6, P = 0.43).

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.