Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse.
Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse.
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DOI：
10.1016/j.yjmcc.2014.09.021
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发表时间：
2014-12
影响因子：
5
通讯作者：
Taro Uchida;Y. Furuno;A. Tanimoto;Y. Toyohira;Kumiko Arakaki;Mika Kina-Tanada;Haruaki Kubota;M. Sakanashi;T. Matsuzaki;K. Noguchi;J. Nakasone;Tomonori Igarashi;S. Ueno;Masayuki Matsushita;S. Ishiuchi;H. Masuzaki;Y. Ohya;N. Yanagihara;H. Shimokawa;Y. Otsuji;M. Tamura;M. Tsutsui
中科院分区：
文献类型：
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作者：
Taro Uchida;Y. Furuno;A. Tanimoto;Y. Toyohira;Kumiko Arakaki;Mika Kina-Tanada;Haruaki Kubota;M. Sakanashi;T. Matsuzaki;K. Noguchi;J. Nakasone;Tomonori Igarashi;S. Ueno;Masayuki Matsushita;S. Ishiuchi;H. Masuzaki;Y. Ohya;N. Yanagihara;H. Shimokawa;Y. Otsuji;M. Tamura;M. Tsutsui
我们研究了肾次全切除术对三种一氧化氮合酶（NOS）缺陷小鼠急性心肌梗死（AMI）发生率的影响。对雄性三重NOS −/−小鼠进行三分之二肾切除术（NX）。早在手术后4个月，2/3 NX就在三重NOS −/−小鼠中引起了AMI引起的心脏性猝死。2/3 NX三重NOS −/−小鼠表现出心电图ST段抬高、心率变异性降低、超声心动图局部室壁运动异常和加速冠状动脉病变形成。心血管危险因素（高血压、高胆固醇血症和高血糖症），循环骨髓来源的血管平滑肌细胞（VSMC）祖细胞数量增加，（一种促动脉炎因子），和心脏基质细胞衍生因子（SDF）-1α的上调（祖细胞的趋化因子）在2/3 NX三重NOS-/- 小鼠，并与血浆血管紧张素II水平（肾素-血管紧张素系统激活的标志物）和尿8-异前列腺素水平（氧化应激的标志物）显著增加相关。重要的是，临床剂量的血管紧张素II 1型受体阻滞剂厄贝沙坦和钙通道拮抗剂利多卡因联合治疗显著预防了冠状动脉病变的形成和AMI的发生，并改善了这些小鼠的预后，沿着改善了所有这些促动脉粥样硬化参数。2/3 NX三重NOS-/-小鼠是一种新的实验上有用的AMI模型。在该模型中，肾素-血管紧张素系统激活、氧化应激、心血管危险因素和SDF-1α诱导的骨髓源性VSMC祖细胞募集似乎参与了AMI的发病机制。
We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs−/−mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs−/−mice as early as 4 months after the surgery. The 2/3NX triple NOSs−/−mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1α (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs−/−mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin–angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs−/−mouse is a new experimentally useful model of AMI. Renin–angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1α-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model.