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

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.

Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

“…However, modulations of a specific GPCR have limits, as diseases are commonly driven by the simultaneous involvement of multiple receptors. Our study identifies Gα13 as the signaling node that regulates metabolic adaptation to extracellular stimuli, as supported by our findings that Gα13 levels in skeletal muscle were repressed by exercise, but increased under metabolic disease conditions, and that the genetic KO facilitated the reprogramming vides metabolic benefits such as the attenuation of diet-induced obesity and atherosclerosis development in mice (51,52). Inhibitors selectively targeting Rock2 or Ser243 phosphorylation of NFATc1 can also be attractive therapeutic candidates for metabolic diseases, as has already been observed in part with a nonselective Rock inhibitor (53).…”

Complement Receptor Targeted Liposomes Encapsulating the Liver X Receptor Agonist GW3965 Accumulate in and Stabilize Atherosclerotic Plaques

“…Macrophage positive area in the plaque was determined by using MOMA2 staining. [ 41 ] Macrophage positive area was calculated as the area positive for the MOMA2 staining divided by the total plaque area for the three largest consecutive sections. Collagen content in the plaques was measured by using Sirius Red staining.…”

Lysophosphatidic acid enhances neointimal hyperplasia following vascular injury through modulating proliferation, autophagy, inflammation and oxidative stress

“…These findings indicated that LPA may contribute to the pathological process of atherosclerosis. In addition, Kritikou et al ( 14 ) suggested that the inhibition of LPA receptors may reduce the size of atherosclerotic plaques. Since LPA serves such a critical role in atherosclerosis, it may be considered a promising therapeutic target for atherosclerosis.…”

“…Furthermore, LPA is associated with various vessel wall cell activities, and contributes to vasculogenesis, angiogenesis and vascular remodeling ( 7 , 10 – 12 ). Indirect evidence that blockade of LPA receptors reduces neointimal hyperplasia has demonstrated that LPA may be involved in neointimal formation following vascular injury and LPA receptor blockade relieves atherosclerotic development ( 13 , 14 ); however, the effects of LPA on neointimal formation remain unclear.…”