Arguing the Case for the Autotaxin–Lysophosphatidic Acid–Lipid Phosphate Phosphatase 3-Signaling Nexus in the Development and Complications of Atherosclerosis

Abstract

The structurally simple glycero- and sphingo-phospholipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), serve as important receptor-active mediators that influence blood and vascular cell function and are positioned to influence the events that contribute to the progression and complications of atherosclerosis. Growing evidence from preclinical, animal models has implicated LPA, LPA receptors, and key enzymes involved in LPA metabolism in pathophysiologic events that may underlie atherosclerotic vascular disease. These observations are supported by genetic analysis in humans implicating a lipid phosphate phosphatase as a novel risk factor for coronary artery disease. In this review we summarize current understanding of LPA production, metabolism and signaling as may be relevant for atherosclerotic and other vascular disease.

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

“…LPA also induces SMC dedifferentiation 50 and may lower expression of CD36 by endothelial cells. 51,52 Consistent with its role in Rho-ROCK signaling, LPA sensitizes murine aortic endothelial cells to oscillatory shear…”

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…LPA can be produced by platelets (Eichholtz et al, 1993), fibroblasts (Fukami and Takenawa, 1992), mitotic neurons (Fukushima et al, 2000), astrocytes (Savaskan et al, 2007) and also cancer cells (Zhao et al, 2010). High concentrations of LPA have been observed in several pathological conditions such as atherosclerosis (Smyth et al, 2014), traumatic brain injury (Crack et al, 2014), spinal cord injury (Santos- Nogueira et al, 2015), different types of cancer (Eder et al, 2000;Lee and Yun, 2010;Zeng et al, 2009;Zhao et al, 2010), neuropsychiatric disorders (Yung et al, 2014) and neuropathic pain (Ahn et al, 2009;Fujita et al, 2007). Production of LPA during inflammation promotes wound-healing and acts to control the proinflammatory environment.…”

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…Remarkably, the tissue content of unsaturated LPA in the small intestine signifi cantly correlated with the extent of aortic atherosclerosis ( 11 ). LPA is emerging as an important signaling molecule in diverse biological processes and disease states , and its role in the pathogenesis of atherosclerosis has been emphasized in recent years (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40).…”