Possible Involvement of Minor Lysophospholipids in the Increase in Plasma Lysophosphatidic Acid in Acute Coronary Syndrome

Abstract

Objective-Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. Approach and Results-We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. Conclusions-Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS. LPA levels were elevated in patients with ACS but not in those with stable angina pectoris (SAP). 16 This result suggested that LPA might be involved in plaque instability and platelet activation in human subjects. In addition, we also found that serum autotaxin levels were not elevated in patients with ACS; LPA is hydrolyzed from lysophosphatidylcholine (LPC) by autotaxin/lysophospholipase D. 17 This discrepancy between LPA and autotaxin interested us greatly because autotaxin is a key enzyme in the production of LPA. Actually, we previously reported a strong positive correlation between LPA and autotaxin in healthy subjects, 18 patients with chronic hepatitis, 19 and patients with follicular lymphoma.20 Therefore, the discordance between ACS subjects and other subjects prompted us to investigate the origins of the elevation in LPA in patients with ACS.LPA is structurally composed of a fatty acid linked to snglycerol-3 phosphate, and the molecular species of the fatty acid chain are varied and determine the molecular species of LPA. In a previous report, 16 we measured the total LPA and LPC levels using previously described enzymatic methods. 21 Using these methods, we could not obtain any information concerning which molecular species of LPA were elevated in patients with ACS. To overcome this limitation, we determined th...

Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces

“…Our results indicated that endothelia exposed to disturbed flow are primed to LPA stimulation which might be further augmented by additional atherogenic factors since LPA is produced during mild oxidation of LDL and accumulates in human atherosclerotic plaques 25 . Recently, plasma long-chain unsaturated LPA was reported to be elevated in patients with acute coronary syndrome 26 . Indeed, our data demonstrate a sensitized inflammation in PPAP2B-deficient cells treated with LPA but not TNFα.…”

“…Abnormal activation of LPA signaling is implicated in various human diseases such as cancer, fibrotic disorders, metabolic syndrome, and cardiovascular diseases 22-24 . LPA accumulates in human atherosclerotic plaques 25 and plasma LPA is elevated in patients with acute coronary syndrome 26 . In ApoE-deficient mice, systemic inhibition of LPA receptors employing pharmacological antagonists notably reduced the atherosclerotic burden 27 .…”

Lysophospholipid Receptors, as Novel Conditional Danger Receptors and Homeostatic Receptors Modulate Inflammation—Novel Paradigm and Therapeutic Potential

“…The role of LPLs in chronic inflammatory disorders such as coronary artery disease (CAD), hypertension [18,19], atherosclerosis and severe vascular diseases is well established [20,21]. Furthermore, LPLs contribute to pathophysiology of autoimmune disorders such as rheumatoid arthritis, and is involved in exacerbating the progression of the disease [22,23].…”

Reduced rat plasma lysophosphatidylglycerol or lysophosphatidic acid level as a biomarker of aristolochic acid-induced renal and adipose dysfunctions

“…Human plasma was reported to contain phosphatidylglycerol at about 300 nM [33], and LPG at about 250 nM [34]. It should be mentioned that evidence for LPG acyltransferase 1 as having the strongest association with body mass index in the full-heritage Pima Indians having a high rate of obesity has been reported [35].…”

“…A previous analytical study on plasma LPA in patients with acute coronary syndrome, showed that 18:2 LPA is produced by the lysoPLD action of ATX, whereas 20:4 LPA and 22:6 LPA are mainly derived from a platelet-related route and from unknown route, respectively. They also suggested lysophoshatidylethanolamine and LPG are possible as precursors of 20:4 LPA and 22:6 LPA, respectively [34], while it is uncertain why other molecular species of LPG were not converted to corresponding LPAs. In connection to these previous findings, our finding showing higher sensitivity to the dietary salt concentration of the 22:6 LPA plasma levels in both AA-treated and untreated rats should be mentioned.…”