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PMID:17069818

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Citation

Luchtefeld, M, Bandlow, N, Tietge, UJ, Grote, K, Pfeilschifter, J, Kaszkin, M, Beck, S, Drexler, H and Schieffer, B (2007) Angiotensin II type 1-receptor antagonism prevents type IIA secretory phospholipase A2-dependent lipid peroxidation. Atherosclerosis 194:62-70

Abstract

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.

Links

PubMed Online version:10.1016/j.atherosclerosis.2006.09.024

Keywords

Angiotensin II Type 1 Receptor Blockers/administration & dosage; Animals; Aorta/cytology; Biphenyl Compounds/administration & dosage; Cells, Cultured; Coronary Artery Disease/drug therapy; Coronary Artery Disease/metabolism; Coronary Artery Disease/pathology; Enzyme Activation/drug effects; Enzyme Activation/physiology; Enzyme Inhibitors/pharmacology; Female; Group II Phospholipases A2/antagonists & inhibitors; Group II Phospholipases A2/blood; Group II Phospholipases A2/metabolism; Humans; Hypertension/drug therapy; Hypertension/metabolism; Hypertension/pathology; Indoles/pharmacology; Lipid Peroxidation/drug effects; Lipid Peroxidation/physiology; Lipoproteins, LDL/metabolism; Losartan/pharmacology; Male; Muscle, Smooth, Vascular/cytology; Myocytes, Smooth Muscle/cytology; Myocytes, Smooth Muscle/drug effects; Myocytes, Smooth Muscle/enzymology; RNA, Messenger/metabolism; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1/genetics; Receptor, Angiotensin, Type 1/metabolism; Tetrazoles/administration & dosage

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PA2GA

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:AGTR1

involved_in

GO:0034374: low-density lipoprotein particle remodeling

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AGTR1

involved_in

GO:0032430: positive regulation of phospholipase A2 activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PA2GA

involved_in

GO:0006644: phospholipid metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PA2GA

part_of

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PA2GA

enables

GO:0004623: phospholipase A2 activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ANGT

involved_in

GO:0034374: low-density lipoprotein particle remodeling

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete


See also

References

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