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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

我们首先检测了小鼠股动脉钢丝损伤后利钠肽受体（ANP、BNP、CNP）的表达。钢丝损伤3周后，新生内膜中GC-A（ANP和BNP受体）和GC-B（CNP受体）均有明显表达，且GC-A的表达水平高于GC-B。当在野生型和GC-A基因敲除小鼠之间比较导丝损伤诱导的新生内膜形成的程度时，GC-A基因敲除小鼠的新生内膜面积更大。提示心脏释放的内源性ANP和BNP可能抑制了钢丝损伤后股动脉的粥样硬化性改变。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血管形成中的作用，在野生型和GC-A基因敲除小鼠中制备下肢缺血模型，并评价血流的恢复。在野生型小鼠中，3周后血流量恢复到约70%。另一方面， ...更多信息 GC-A基因敲除小鼠血流量恢复率约为20%，约一半的小鼠出现下肢坏死。提示内源性ANP和BNP可能在缺血性血管新生中起重要作用。根据这些结果，设计体外研究以研究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的环GMP（cGMP）积累。结果表明，ANP和BNP刺激后，细胞内cGMP水平显著升高，表明这些肽对内皮祖细胞具有直接作用。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，而且还参与促进这些病变中的新生血管形成。因此，本研究为利用ANP和BNP的促细胞分化作用进行抗动脉粥样硬化治疗的临床应用提供了重要进展。我们将对CNP、肾上腺髓质素和生长素释放肽的抗动脉粥样硬化作用和治疗应用作进一步的研究。少