Effects of natriuretic peptides on the mechanisms of atherosclerosis

利钠肽对动脉粥样硬化机制的影响

• 批准号: 05670622
• 负责人: KUGIYAMA Kiyotaka
• 金额: $ 1.41万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670622/
• 关键词: Natriuretic Peptides; Neutral Endopeptidase; Atherosclerosis; Endothelial cell; Oxysterol; Oxidized LDL,; Lysophosphatidylcholine; Oxidized LDL; Endothelial cells; Oxidized IDL

Neutral Endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter the functions of smooth muscle cell or macrophage in the arterial wall. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (Candoxatril ; UK), an orally active inhibitor of NEP,on the development of atherosclerotic changes in high cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks : normal rabbit diet (Nor, n=15), 1.5% cholesterol diet (Chol, n=15), or 1.5% choresterol diet containing UK (20 mg/kg/day) (UK +Chol, n=15). At the end of dietary period, UK-treatment suppressed surface area of the aorta covered by plaques (% surface area : Chol 48 + 7% vs UK + chol 11 + 3, p<0.05) and decreased contents of cholesterol and cholesterol ester in the aortas. UK also reduced plasma total cholesterol by 15 + 4% of Chol (1680 + 180 mg/dl). UK-treatment preserved endothelium-dependent relaxation of the isolated thoracic aortic rings suspended in the organ chamber in response to acetylcholine (ACh) (EC50, nM ; concentrations of ACh causing 50% inhibition of contractions with 0.3 mM of phenylephrine : Nor 12 + 4, Chol 360 + 20 +, UK + Chol 56 + 9^*, +p<0.01 vs Nor, ^*p<0.01 vs Chol). UK-treatment decreased plasma NEP enzymatic activity by 27 + 3% of Chol and prevented the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings in the organ chamber in response to atrial natriuretic peptide, one of NEP substrates (EC50, pM : Nor 50 + 4, Chol 290 + 20 +, UK + Chol 65 + 8, +p<0.01 vs Nor, ^*p<0.01 vs Chol). The results suggest that NEP plays a significant role in atherogenesis and NEP inhibitors might be therapeutically useful in the prevention of atherosclerosis.

中性内肽酶24.11(NEP)广泛分布于体内，能对多种内源性血管活性多肽进行降解和失活，其中一些内源性血管活性多肽可以改变动脉壁中的平滑肌细胞或巨噬细胞的功能。本研究的目的是评价口服NEP活性抑制剂UK79300(Candoxtril；UK)对高胆固醇喂养兔动脉粥样硬化形成的影响。雄性新西兰大白兔饲喂8周：正常兔饲料(NOR，n=15)、1.5%胆固醇饲料(Chol，n=15)或含UK的1.5%Choresterol饲料(20 mg/kg/d)(UK+Chol，n=15)。在饲粮结束时，UK处理组大鼠的主动脉表面积被斑块覆盖(%表面积：Chol 48±7%vs UK+Chol 11+3，p&lt；0.05)，并降低了主动脉中胆固醇和胆固醇酯的含量。UK还将血浆总胆固醇降低了15+4%的Chol(1680+180 mg/dl)。UK处理保留了对乙酰胆碱(ACh)(EC50，NM；0.3 mM苯肾上腺素可抑制50%收缩的ACh浓度：NOR 12+4，Chol 360+20+，UK+Chol 56+9^*，+p&lt；0.01vs Nor，^*p&lt；0.01vs Chol)的血管内皮依赖性的松弛作用。UK处理使血浆NEP酶活性降低27+3%，并防止心钠素(NEP底物之一，EC50，PM：NOR 50+4，Chol 290+20+，UK+Chol 65+8，+p&lt；0.01vs Nor，^*p&lt；0.01vs Chol)对器官腔内离体胸主动脉环松弛的动脉粥样硬化损害。结果提示，NEP在动脉粥样硬化形成中起重要作用，NEP抑制剂可能在预防动脉粥样硬化方面有一定的应用价值。

项目成果

Hirofumi Yasue: "Localization and Mechanisms of Secretion of B-type Natriuretic Peptide(BNP)in Comparison Peptide(ANP)in Normal Subjects and Patients With Heart Failure" Circulation. 90. 195-203 (1994)

Hirofumi Yasue：“正常受试者和心力衰竭患者的比较肽（ANP）中 B 型钠尿肽（BNP）分泌的定位和机制”循环。

Hirofumi Yasue, Kiyotaka Kugiyama, et al.: "Localization and mechanisms of secretion of B-type natriuretic peptide (BNP) in comparison with those of A-type natriuretic peptide (ANP) in normal subjects and patients with heart failure." Circulation. 90. 195

Hirofumi Yasue、Kiyotaka Kugiyama 等人：“在正常受试者和心力衰竭患者中，与 A 型利钠肽 (ANP) 相比，B 型利钠肽 (BNP) 的定位和分泌机制。”

Seigo Sugiyama: "Lysophosphatidylcholine in oxidized low-density lipoprotein increases endothelial susceptibility to polymorphonuclear leukocyte-induced endothe-lial dysfunction in porcine coronary arteries:role of protein kinase C" Circulation Research.

Seigo Sugiyama：“氧化低密度脂蛋白中的溶血磷脂酰胆碱增加了猪冠状动脉内皮对多形核白细胞诱导的内皮功能障碍的敏感性：蛋白激酶 C 的作用”循环研究。

Toyoaki Murohara: "Cigarette Smoke Extract Contracts Isolated Porcine Coronary Arteries by Superoxide Anion-mediated Degradation of EDRF" Am J Physiol. 266. H874-H880 (1994)

Toyoaki Murohara：“香烟烟雾提取物通过超氧阴离子介导的 EDRF 降解使离体猪冠状动脉收缩”Am J Physiol。

Toyoaki Murohara, Kiyotaka Kugiyama, et al.: "LPC in oxidized LDL elicits vasoconstriction and inhibits endothelium - dependent relaxation." Am J Physiol. 267. H2441-H2449 (1994)

Toyoaki Murohara、Kiyotaka Kugiyama 等人：“氧化 LDL 中的 LPC 会引起血管收缩并抑制内皮依赖性松弛。”