Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3β activation
Tissue kallikrein protects against pressure overload-induced cardiac hypertrophy through kinin B2 receptor and glycogen synthase kinase-3β activation
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DOI：
10.1016/j.cardiores.2006.10.014
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发表时间：
2007-01-01
影响因子：
10.8
通讯作者：
Chao, Julie
中科院分区：
文献类型：
--
作者：
Li, Huey-Jiun;Yin, Hang;Chao, Julie
目的：我们评估了糖原合成酶激酶-3 β方法：采用组织激肽释放酶抑制剂GSK-3 β（GSK-3 β）和激肽B2受体介导的大鼠心肌肥厚模型及激肽B1、B2受体缺失的小鼠心肌肥厚模型，研究组织激肽释放酶对心肌肥厚的保护作用及其机制。心肌内递送含有人组织激肽释放酶基因的腺病毒导致重组激肽释放酶在大鼠心肌中的表达。在AC后28天，激肽释放酶基因递送改善了心脏功能，降低了心脏重量/体重比和心肌细胞大小，而不影响平均动脉压。艾替班和携带催化失活GSK-3 β突变体的腺病毒（Ad. GSK-3 β-KM）消除了激肽释放酶的作用。激肽释放酶治疗增加了心脏一氧化氮（NO）水平，降低了NAD（P）H氧化酶活性和超氧化物的产生。此外，激肽释放酶降低了心肌中凋亡信号调节激酶1、丝裂原活化蛋白激酶（MAPK）、Akt、GSK-3 β和cAMP反应元件结合（CREB）蛋白的磷酸化，并降低了核因子-κ B（NF-κ B）活化。Ad.GSK-3 β-KM消除了激肽释放酶对GSK-3 β和CREB磷酸化以及NF-κ B活化的作用，而艾替班特阻断了所有激肽释放酶的作用。在激肽B2受体敲除小鼠中进一步证实了激肽B2受体在心肌肥大中的保护作用，与野生型和B1受体敲除小鼠相比，AC后激肽B2受体敲除小鼠的心脏重量/体重比和心肌细胞大小显著增加。这些发现表明，组织激肽释放酶，通过激肽B2受体和GSK-3 β信号，通过增加NO形成和氧化应激诱导的Akt-GSK-3 β介导的信号传导事件、MAPK和NF-κ B活化来防止压力超负荷诱导的心肌细胞肥大。(c)2006年欧洲心脏病学会。由爱思唯尔公司出版
Objective: We assessed the role of glycogen synthase kinase-3 beta (GSK-3 beta) and kinin B2 receptor in mediating tissue kallikrein's protective effects against cardiac hypertrophy.Methods: We investigated the effect and mechanisms of tissue kallikrein using hypertrophic animal models of rats as well as mice deficient in kinin B1 or B2 receptor after aortic constriction (AC).Results: Intramyocardial delivery of adenovirus containing the human tissue kallikrein gene resulted in expression of recombinant kallikrein in rat myocardium. Kallikrein gene delivery improved cardiac function and reduced heart weight/body weight ratio and cardiomyocyte size without affecting mean arterial pressure 28 days after AC. Icatibant and adenovirus carrying a catalytically inactive GSK-3 beta mutant (Ad. GSK-3 beta-KM) abolished kallikrein's effects. Kallikrein treatment increased cardiac nitric oxide (NO) levels and reduced NAD(P)H oxidase activity and superoxide production. Furthermore, kallikrein reduced the phosphorylation of apoptosis signal-regulating kinase 1, mitogen-activated protein kinases (MAPKs), Akt, GSK-3 beta, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-kappa B (NF-kappa B) activation in the myocardium. Ad.GSK-3 beta-KM abrogated kallikrein's actions on GSK-3 beta and CREB phosphorylation and NF-kappa B activation, whereas icatibant blocked all kallikrein's effects. The protective role of kinin B2 receptor in cardiac hypertrophy was further confirmed in kinin receptor knockout mice as heart weight/body weight ratio and cardiomyocyte size increased significantly in kinin B2 receptor knockout mice after AC compared to wild type and B1 receptor knockout mice.Conclusions: These findings indicate that tissue kallikrein, through kinin B2 receptor and GSK-3 beta signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3 beta-mediated signaling events, MAPK and NF-kappa B activation. (c) 2006 European Society of Cardiology. Published by Elsevier B.V.