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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.


LPA1/3 inhibition reduces total cholesterol content in the serum.(a) The animal body weight showed no significant differences throughout 6 weeks of treatment between the groups. (b) Total serum cholesterol remained at significantly lower levels in the Ki16425 group compared to the control. (c) The Ki16425 treated animals presented a trend towards reduced LDL levels (P = 0.06). P-values are calculated by the fraction sum for each lipoprotein per group (n = 5/grp). All values are depicted as mean ± SEM (*P < 0.05).
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f2: LPA1/3 inhibition reduces total cholesterol content in the serum.(a) The animal body weight showed no significant differences throughout 6 weeks of treatment between the groups. (b) Total serum cholesterol remained at significantly lower levels in the Ki16425 group compared to the control. (c) The Ki16425 treated animals presented a trend towards reduced LDL levels (P = 0.06). P-values are calculated by the fraction sum for each lipoprotein per group (n = 5/grp). All values are depicted as mean ± SEM (*P < 0.05).

Mentions: LPA1/3 inhibition with Ki16425 did not alter body weight (Fig. 2a) and similarly, analysis of the liver weight or spleen weight at the endpoint of the study presented no change for the treated versus the control group (Supplementary Fig. 1a,b). Interestingly, total serum cholesterol levels in time upon LPA1/3 inhibition, was significantly lower compared to the control group (Fig. 2b, w3: −20%, P = 0.012; w6: −16%, P = 0.017). Further analysis of the serum lipoprotein content at the experimental endpoint showed a trend towards decreased LDL levels for the Ki16425 treated mice as compared to the control (Fig. 2c, P = 0.06).


Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice
LPA1/3 inhibition reduces total cholesterol content in the serum.(a) The animal body weight showed no significant differences throughout 6 weeks of treatment between the groups. (b) Total serum cholesterol remained at significantly lower levels in the Ki16425 group compared to the control. (c) The Ki16425 treated animals presented a trend towards reduced LDL levels (P = 0.06). P-values are calculated by the fraction sum for each lipoprotein per group (n = 5/grp). All values are depicted as mean ± SEM (*P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: LPA1/3 inhibition reduces total cholesterol content in the serum.(a) The animal body weight showed no significant differences throughout 6 weeks of treatment between the groups. (b) Total serum cholesterol remained at significantly lower levels in the Ki16425 group compared to the control. (c) The Ki16425 treated animals presented a trend towards reduced LDL levels (P = 0.06). P-values are calculated by the fraction sum for each lipoprotein per group (n = 5/grp). All values are depicted as mean ± SEM (*P < 0.05).
Mentions: LPA1/3 inhibition with Ki16425 did not alter body weight (Fig. 2a) and similarly, analysis of the liver weight or spleen weight at the endpoint of the study presented no change for the treated versus the control group (Supplementary Fig. 1a,b). Interestingly, total serum cholesterol levels in time upon LPA1/3 inhibition, was significantly lower compared to the control group (Fig. 2b, w3: −20%, P = 0.012; w6: −16%, P = 0.017). Further analysis of the serum lipoprotein content at the experimental endpoint showed a trend towards decreased LDL levels for the Ki16425 treated mice as compared to the control (Fig. 2c, P = 0.06).

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.