Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation and modification of low density lipoproteins (LDL) within the vessel wall represent key events in atherogenesis. Secretory phospholipase A2 type IIA (sPLA2-IIA) modulates the enzymatic process of LDL-modification and was recently identified as an independent predictor of coronary events in patients with coronary artery disease (CAD). Angiotensin II (ANG II) type 1 (AT1)-receptor blockade reduces LDL-modification and atherosclerotic plaque formation in rodent and primate models of atherosclerosis. Therefore, we assessed whether ANG II via its AT1-receptor enhances sPLA2-IIA-dependent lipid peroxidation in vitro and in patients with CAD. Stimulation of rat aortic smooth muscle cells with ANG II (10(-7) mol/L) enhanced sPLA2-IIA protein expression, activity as well as LDL-peroxidation, determined by western blot, activity assay and malondialdehyde (MDA)-assay and diene formation, respectively, and were blunted by AT1-receptor blockade (Losartan, 10(-5) mol/L). In addition, ANG II-induced sPLA2 activity and LDL-peroxidation were abolished by the sPLA2-IIa activity inhibitor LY311727 (10(-5) mol/L). To evaluate a potential clinical implication, patients (n=18) with angiographically documented CAD were treated with the AT1-receptor blocker Irbesartan (IRB; 300 mg/d) for 12 weeks. Blood samples were obtained from patients pre- and post-treatment and from healthy volunteers. SPLA2-IIA serum level and activity, circulating antibodies against oxidized LDL (oxLDL), oxLDL and MDA were determined in patients and found to be significantly increased compared to healthy volunteers. IRB therapy reduced these markers of inflammation, whereas total cholesterol, HDL- and LDL-fractions remained unchanged. ANG II may elicit pro-atherosclerotic effects via type IIA sPLA2-dependent LDL-modifications. Chronical AT1-receptor blockade reduces sPLA2-IIA level and activity and subsequently lipid peroxidation. Theses findings represent a novel anti-atherosclerotic mechanism and imply that AT1-receptor blockade elicits anti-atherosclerotic potencies even in the absence of plasma cholesterol reduction.
Atherosclerosis 2007 Sep
PMID:Angiotensin II type 1-receptor antagonism prevents type IIA secretory phospholipase A2-dependent lipid peroxidation. 1706 18

Among the many mammalian secreted phospholipase A2 (sPLA2) enzymes, PLA2G3 (group III secreted phospholipase A2) is unique in that it possesses unusual N- and C-terminal domains and in that its central sPLA2 domain is homologous to bee venom PLA2 rather than to other mammalian sPLA2s. To elucidate the in vivo actions of this atypical sPLA2, we generated transgenic (Tg) mice overexpressing human PLA2G3. Despite marked increases in PLA2 activity and mature 18-kDa PLA2G3 protein in the circulation and tissues, PLA2G3 Tg mice displayed no apparent abnormality up to 9 months of age. However, alterations in plasma lipoproteins were observed in PLA2G3 Tg mice compared with control mice. In vitro incubation of low density (LDL) and high density (HDL) lipoproteins with several sPLA2s showed that phosphatidylcholine was efficiently converted to lysophosphatidylcholine by PLA2G3 as well as by PLA2G5 and PLA2G10, to a lesser extent by PLA2G2F, and only minimally by PLA2G2A and PLA2G2E. PLA2G3-modified LDL, like PLA2G5- or PLA2G10-treated LDL, facilitated the formation of foam cells from macrophages ex vivo. Accumulation of PLA2G3 was detected in the atherosclerotic lesions of humans and apoE-deficient mice. Furthermore, following an atherogenic diet, aortic atherosclerotic lesions were more severe in PLA2G3 Tg mice than in control mice on the apoE-null background, in combination with elevated plasma lysophosphatidylcholine and thromboxane A2 levels. These results collectively suggest a potential functional link between PLA2G3 and atherosclerosis, as has recently been proposed for PLA2G5 and PLA2G10.
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PMID:Analyses of group III secreted phospholipase A2 transgenic mice reveal potential participation of this enzyme in plasma lipoprotein modification, macrophage foam cell formation, and atherosclerosis. 1880 41