Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice
Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice
复制标题
DOI：
10.1161/01.hyp.0000173420.31354.ef
复制
发表时间：
2005-08-01
期刊：
影响因子：
8.3
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Nakanishi, M;Saito, Y;Nakao, K
虽然血浆心钠素（ANP）和脑钠素（BNP）水平在心肌梗死（MI）后早期升高，但其意义尚不完全清楚。因此，我们研究了利钠肽在缺乏利钠肽受体鸟苷酸环化酶-A（ANP和BNP的受体）的敲除（KO）小鼠中诱导MI后的功能。对KO和野生型（WT）小鼠进行左冠状动脉结扎，然后随访4周。无论基因型如何，几乎所有的死亡都发生在诱导MI后1周内。KO小鼠显示出显著更高的死亡率，因为急性心力衰竭的发生率更高，这与水和钠排泄减少以及编码ANP、BNP、转化生长因子β 1和I型胶原蛋白的mRNA的心脏水平更高有关。梗死后4周，KO小鼠的左心室重塑（包括心肌肥大和纤维化）和左心室收缩功能受损明显比WT小鼠严重。值得注意的是，在KO小鼠中观察到的增强的心肌纤维化在梗死的双KO小鼠中几乎不存在，缺乏鸟苷酸环化酶-A和血管紧张素II 1a型受体，尽管存活率没有改善，心脏肥大也没有减弱。因此，内源性心脏利钠肽激活鸟苷酸环化酶-A可预防急性心力衰竭并减弱MI后的慢性心脏重塑。这些有益作用部分是通过抑制肾素-血管紧张素系统（RAS）介导的，尽管也建议鸟苷酸环化酶-A的RAS独立保护作用。
Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout ( KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-beta 1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.