Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury
Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/NG-nitro-L-arginine methyl ester-induced myocardial injury
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DOI：
10.1161/01.cir.0000097000.51723.6f
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发表时间：
2003-11-18
期刊：
影响因子：
37.8
通讯作者：
Adler, GK
中科院分区：
文献类型：
--
作者：
Oestreicher, EM;Martinez-Vasquez, D;Adler, GK
背景：血管紧张素II （Ang II）增加醛固酮和纤溶酶原激活物抑制剂-1 （PAI-1）的水平。醛固酮和PAI-1似乎都促进心血管（CV）损伤。我们的目的是确定PAI-1和醛固酮在高angii和低一氧化氮（NO）可用性模型中心肌和肾脏损害发展中的作用，这种模式见于心力衰竭、糖尿病和动脉硬化患者。方法与结果：中高钠饮食小鼠给予NO合成酶抑制剂n - g -硝基- l -精氨酸甲酯（L-NAME）治疗14 d，并在第8 ~ 14天给予Ang II。使用矿物皮质激素受体拮抗剂螺内酯（0、1.5、15和50 mg.100 g(-1)）评估醛固酮和PAI-1在CV损伤发展中的作用。day（-1）和PAI-1缺失小鼠（-/-）。Ang II/ l - name处理的小鼠表现为肾小球缺血、蛋白尿、肌细胞和血管平滑肌细胞坏死，并伴有相关的混合炎症反应、疏松胶原沉积和新生血管。与饮用盐水的小鼠相比，Ang II/ l - name处理的小鼠心脏体重比（HW/BW）显著增加，心脏和肾脏损害（通过组织学检查评估）、PAI-1免疫反应性和蛋白尿。螺内酯治疗降低PAI-1免疫反应性，并以剂量依赖性方式减少心脏和肾脏损害。PAI-1（-/-）动物的CV损伤程度与PAI-1（-/-）动物相似。结论-矿化皮质激素受体拮抗剂，而非PAI-1缺乏，可保护小鼠发生Ang II/ l - name介导的心肌和血管损伤和蛋白尿，提示醛固酮，而非PAI-1，在早期Ang II/ l - name诱导的心血管损伤中起关键作用。
Background-Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis.Methods and Results-Mice on a moderately high sodium diet were treated with the NO synthase inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg.100 g(-1).day(-1)) and PAI-1-deficient mice (PAI-1(-/-)). Ang II/L-NAME-treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME-treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1(-/-) animals had a similar degree of CV injury as PAI-1(-/-) animals.Conclusions-Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury.