Antiatherosclerotic therapy using cell differentiation-promoting effect of biologically active peptides

利用生物活性肽的细胞分化促进作用进行抗动脉粥样硬化治疗

基本信息

批准号：
18590829
负责人：
HORIO Takeshi
金额：
$ 2.49万
依托单位：
National Cardiovascular Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590829/
关键词：
Atherosclerosis Natriuretic peptides Neovascularization 平滑筋細胞

项目摘要

We first examined the expression of receptors for natriuretic peptides(ANP, BNP, CNP) in wire-injured femoral arteries in mice. Significant expressions of both GC-A(receptor for ANP and BNP) and GC-B(receptor for CNP) were found in neointima after 3 weeks of wire injury, and the expression level of GC-A was higher than that of GC-B. When the extent of wire injury-induced neointima formation was compared between wild-type and GC-A knockout mice, the area of neointima was greater in GC-A knockout mice. This result suggested the possibility that endogenous ANP and BNP released from the heart inhibited atherosclerotic change of femoral artery after wire injury. To further examine the role of endogenous ANP and BNP in neovascularization observed in atherosclerotic lesions, lower limb-ischemic model was made in both wild-type and GC-A knockout mice, and the recovery of blood flow was evaluated. The blood flow was restored to about 70% after 3 weeks in wild-type mice. On the other hand, inter … More estingly, the recovery rate of blood flow in GC-A knockout mice was about 20%, and approximately half of them had necrotized lower limbs. The finding suggested that endogenous ANP and BNP might play an important role in the angiogenesis in ischemic lesions. From these results, an in vitro study was designed to investigate whether ANP and BNP, stimulate cyclic GMP(cGMP) accumulation in vascular endothelial progenitor cells derived from human blood mononuclear cells. As a result, intracellular cGMP levels were remarkably elevated after stimulation with ANP and BNP, suggesting that these peptides have a direct effect on endothelial progenitor cells. Our findings indicate that endogenous ANP and BNP are involved not only in the inhibition of the formation of atherosclerotic lesions, but also in the promotion of neovascularization in those lesions. Thus, the present study provided a great progress forclinical application of antiatherosclerotic therapy using cell differentiation-promoting effect of ANP and BNP. We will forward further investigations about antiatherosclerotic effects and therapeutic application of CNP, adrenomedulin, and ghrelin. Less

我们首先检测了钢丝损伤小鼠股动脉中利钠肽受体（ANP、BNP、CNP）的表达，GC-A（ANP 和 BNP 受体）和 GC-B（CNP 受体）均显着表达。线损伤3周后新生内膜中发现GC-A的表达水平高于线损伤程度时的GC-B。比较野生型和GC-A敲除小鼠的新内膜形成，GC-A敲除小鼠的新内膜面积更大，这一结果提示心脏释放的内源性ANP和BNP抑制股动脉粥样硬化变化的可能性。为了进一步研究内源性 ANP 和 BNP 在动脉粥样硬化病变中观察到的新生血管形成中的作用，在野生型和 GC-A 敲除中制作了下肢缺血模型。野生型小鼠的血流恢复率在3周后恢复到70%左右。大约20%的小鼠出现下肢坏死，这一发现表明内源性ANP和BNP可能在缺血性病变的血管生成中发挥重要作用。根据这些结果，设计了一项体外研究。研究ANP和BNP是否刺激源自人血液单核细胞的血管内皮祖细胞中环鸟苷酸（cGMP）的积累，结果是，在用ANP和BNP刺激后，细胞内的环鸟苷酸（cGMP）水平显着升高，表明这些肽具有直接作用。我们的研究结果表明，内源性 ANP 和 BNP 不仅参与抑制动脉粥样硬化病变的形成，而且还参与促进动脉粥样硬化病变的形成。因此，本研究为ANP和BNP的细胞分化促进作用的抗动脉粥样硬化治疗的临床应用提供了重大进展，我们将进一步研究CNP、肾上腺髓质素和ghrelin的抗动脉粥样硬化作用和治疗应用。