Kallikrein-kinin in stroke, cardiovascular and renal disease
Kallikrein-kinin in stroke, cardiovascular and renal disease
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DOI：
10.1113/expphysiol.2004.028464
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发表时间：
2005-05-01
影响因子：
2.7
通讯作者：
Chao, L
中科院分区：
文献类型：
--
作者：
Chao, J;Chao, L
组织激肽释放酶是一种丝氨酸蛋白酶，能从激肽原底物中产生强有力的血管扩张剂激肽肽。组织激肽释放酶的水平在患有高血压、心血管和肾脏疾病的人和动物模型中降低。利用转基因和体细胞基因转移的方法，我们研究了组织激肽释放酶-激肽系统在心血管，肾脏和中枢神经系统中的作用。单次注射质粒DNA或腺病毒载体中的人组织激肽释放酶基因导致几种高血压动物模型的心脏和肾脏中的血压延长降低和肥大和纤维化减弱。此外，基因转移后增强的激肽释放酶-激肽水平发挥了有益的作用，在血压正常的动物模型中保护心脏重塑、肾损伤、再狭窄、脑梗死和神经功能缺损，而没有血液动力学作用，表明激肽释放酶的直接作用不依赖于其降低血压的能力。激肽释放酶的作用由激肽B2受体介导，因为特异性B2受体拮抗剂艾替班特消除了激肽释放酶的作用。此外，激肽释放酶-激肽通过抑制细胞凋亡、炎症、肥大和纤维化，以及促进心、肾、脑和血管中的血管生成和神经发生而表现出多效性作用。外源性施用激肽释放酶还导致一氧化氮（NO）/cGMP和cAMP水平增加，并降低NAD（P）H氧化酶活性、超氧化物形成和促炎细胞因子水平。这些结果表明激肽释放酶-激肽通过激肽B2受体作为抗氧化剂和抗炎剂在预防中风、心血管和肾脏疾病中的新作用，并可能揭示用于预防和治疗人类心力衰竭、血管损伤、终末期肾脏疾病和中风的新药物靶点。
Tissue kallikrein, a serine proteinase, produces the potent vasodilator kinin peptide from kininogen substrate. The levels of tissue kallikrein are reduced in humans and animal models with hypertension, cardiovascular and renal disease. Using transgenic and somatic gene transfer approaches, we investigated the role of the tissue kallikrein-kinin system in cardiovascular, renal and central nervous systems. A single injection of the human tissue kallikrein gene in plasmid DNA or an adenoviral vector resulted in a prolonged reduction of blood pressure and attenuation of hypertrophy and fibrosis in the heart and kidney of several hypertensive animal models. Furthermore, enhanced kallikrein-kinin levels after gene transfer exerted beneficial effects, with protection against cardiac remodelling, renal injuries, restenosis, cerebral infarction and neurological deficits in normotensive animal models without haemodynamic effects, indicating direct actions of kallikrein independent of its ability to lower blood pressure. The effects of kallikrein were mediated by the kinin B2 receptor, as the specific B2 receptor antagonist icatibant abolished the actions of kallikrein. Moreover, kallikrein-kinin exhibited pleiotropic effects by inhibiting apoptosis, inflammation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in the heart, kidney, brain and blood vessel. Exogenous administration of kallikrein also led to increased nitric oxide (NO)/cGMP and cAMP levels, and reduced NAD(P)H oxidase activities, superoxide formation and pro-inflammatory cytokine levels. These results indicate a novel role of kallikrein-kinin through the kinin B2 receptor as an antioxidant and anti-inflammatory agent in protection against stroke, cardiovascular and renal disease, and may uncover new drug targets for the prevention and treatment of heart failure, vascular injury, end-stage renal disease and stroke in humans.