Heparin Cofactor II Protects Against Angiotensin II-Induced Cardiac Remodeling Via Attenuation of Oxidative Stress in Mice
Heparin Cofactor II Protects Against Angiotensin II-Induced Cardiac Remodeling Via Attenuation of Oxidative Stress in Mice
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DOI：
10.1161/hypertensionaha.110.152207
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发表时间：
2010-09-01
期刊：
影响因子：
8.3
通讯作者：
Matsumoto, Toshio
中科院分区：
文献类型：
--
作者：
Sumitomo-Ueda, Yuka;Aihara, Ken-ichi;Matsumoto, Toshio
肝素辅因子II（HCII）是一种丝氨酸蛋白酶抑制剂，在与血管系统细胞外基质中的硫酸皮肤素蛋白聚糖结合后抑制组织凝血酶作用。我们以前报道过，杂合子HCII缺陷（HCII +/-）的人类和小鼠表现出血管重塑，包括动脉粥样硬化的加速。然而，HCII对心脏重塑的作用从未被确定。通过渗透微型泵向25周龄的HCII +/+和HCII +/-小鼠输注血管紧张素II（Ang II; 2.0 mg/kg/d）2周。超声心动图显示HCII +/-小鼠的心脏向心性重构加速，HCII +/-小鼠的左心房容积大于HCII +/+小鼠。组织学研究显示，HCII +/-小鼠的左心房和左心室中的间质纤维化比HCII +/+小鼠更显著。与HCII +/+小鼠相比，Ang II处理的HCII +/-小鼠中8-羟基-2 '脱氧鸟苷（氧化应激的一个参数）和二氢乙烯利阳性斑点（表明心肌中超氧化物的产生）的每日尿排泄量显著增加。心钠肽和脑钠肽、利钠肽家族成员、Nox 4、Rac-1和p67（phox）（作为NAD（P）H氧化酶的组分）以及转化生长因子β 1和前胶原III的心脏基因表达水平在HCII +/-小鼠中比在HCII +/+小鼠中增加更多。然而，人类HCII蛋白的管理衰减所有这些异常在血管紧张素II治疗HCII +/-小鼠。此外，人HCII蛋白补充几乎消除了血管紧张素II治疗的HCII +/+小鼠的心脏纤维化。结果表明，HCII通过抑制NAD（P）H氧化酶-转化生长因子-β 1通路对Ang II诱导的心脏重塑具有保护作用。（高血压。2010; 56：430 - 436.）
Heparin cofactor II (HCII), a serine protease inhibitor, inhibits tissue thrombin action after binding with dermatan sulfate proteoglycans in the extracellular matrix of the vascular system. We previously reported that heterozygous HCII-deficient (HCII+/-) humans and mice demonstrate acceleration of vascular remodeling, including atherosclerosis. However, the action of HCII on cardiac remodeling never has been determined. HCII+/+ and HCII+/- mice at age 25 weeks were infused with angiotensin II (Ang II; 2.0 mg/kg/d) for 2 weeks by an osmotic mini-pump. Echocardiography revealed acceleration of cardiac concentric remodeling in HCII+/- mice and larger left atrial volume in HCII+/- mice than in HCII+/+ mice. Histopathologic studies showed more prominent interstitial fibrosis in both the left atrium and left ventricle in HCII+/- mice than in HCII+/+ mice. Daily urinary excretion of 8-hydroxy-2' deoxyguanosine, a parameter of oxidative stress, and dihydroethidium-positive spots, indicating superoxide production in the myocardium, were markedly increased in Ang II-treated HCII+/- mice compared to those in HCII+/+ mice. Cardiac gene expression levels of atrial natriuretic peptides and brain natriuretic peptides, members of the natriuretic peptide family, Nox 4, Rac-1, and p67(phox) as components of NAD(P) H oxidase, and transforming growth factor-beta 1 and procollagen III were more augmented in HCII+/- mice than in HCII+/+ mice. However, administration of human HCII protein attenuated all of those abnormalities in Ang II-treated HCII+/- mice. Moreover, human HCII protein supplementation almost abolished cardiac fibrosis in Ang II-treated HCII+/+ mice. The results indicate that HCII has a protective role against Ang II-induced cardiac remodeling through suppression of the NAD(P) H oxidase-transforming growth factor-beta 1 pathway. (Hypertension. 2010;56:430-436.)