Angiotensinogen Exerts Effects Independent of Angiotensin II.
Angiotensinogen Exerts Effects Independent of Angiotensin II.
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DOI：
10.1161/atvbaha.115.306740
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Daugherty A
中科院分区：
文献类型：
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作者：
Lu H;Wu C;Howatt DA;Balakrishnan A;Moorleghen JJ;Chen X;Zhao M;Graham MJ;Mullick AE;Crooke RM;Feldman DL;Cassis LA;Vander Kooi CW;Daugherty A
这项研究利用多种遗传和药物操作来确定血管紧张素原(AGT)是否具有血管紧张素II(Ang II)非依赖性作用。所有研究小鼠都处于低密度脂蛋白受体/阴性背景，并以饱和脂肪丰富的饮食喂养。在AGT基因内含子2中有等位基因和新霉素盒的小鼠(即下AGT小鼠)中，血浆AGT浓度比它们的野生型后代低90%。HypoAGT小鼠的SBP更低，动脉粥样硬化更少，体重增加和肝脏脂肪变性减少。在肝细胞特异性AGT缺陷或AGT被反义寡核苷酸(ASO)药物抑制的小鼠中，可再现较低的血浆AGT浓度和所有表型。相反，肾素抑制剂阿利吉伦抑制AGT裂解并不能改变低密度脂蛋白受体-/-小鼠的体重增加和肝脏脂肪变性。在已证实肥胖的小鼠中，服用AGT ASO与阿利吉仑相比，可以同等程度地降低SBP和动脉粥样硬化。给予AGT ASO可停止体重增加并进一步降低体重，而阿利吉仑在持续的饱和脂肪丰富的饮食喂养中不影响体重增加。斑马鱼、小鼠、大鼠和人的AGT蛋白的结构比较发现，在DES(Angi)AGT结构域中有4个高度保守的序列。DES(Angi)AGT通过肝细胞特异性AGT缺陷小鼠中的腺相关病毒感染，增加体重增加和肝脏脂肪变性，但不影响动脉粥样硬化。AGT通过DES(Angi)AGT结构域的功能参与体重增加和肝脏脂肪变性，该结构域独立于Angii的产生。
This study determined whether angiotensinogen (AGT) has angiotensin (Ang)II-independent effects using multiple genetic and pharmacological manipulations. All study mice were in LDL receptor -/- background and fed a saturated fat-enriched diet. In mice with floxed alleles and a neomycin cassette in intron 2 of the AGT gene (hypoAGT mice), plasma AGT concentrations were > 90% lower compared to their wild type littermates. HypoAGT mice had lower SBP, less atherosclerosis, and diminished body weight gain and liver steatosis. Low plasma AGT concentrations and all phenotypes were recapitulated in mice with hepatocyte-specific deficiency of AGT or pharmacological inhibition of AGT by antisense oligonucleotide (ASO) administration. In contrast, inhibition of AGT cleavage by a renin inhibitor, aliskiren, failed to alter body weight gain and liver steatosis in LDL receptor -/- mice. In mice with established adiposity, administration of AGT ASO versus aliskiren led to equivalent reductions of SBP and atherosclerosis. AGT ASO administration ceased body weight gain and further reduced body weight, whereas aliskiren did not affect body weight gain during continuous saturated fat-enriched diet feeding. Structural comparisons of AGT proteins in zebrafish, mouse, rat and human revealed 4 highly conserved sequences within the des(AngI)AGT domain. des(AngI)AGT, through adeno-associated viral infection in hepatocyte-specific AGT deficient mice, increased body weight gain and liver steatosis, but did not affect atherosclerosis. AGT contributes to body weight gain and liver steatosis through functions of the des(AngI)AGT domain, which are independent of AngII production.