心血管疾病治疗的新靶点——Rho激酶

宫丽丽;方莲花;杜冠华

中国药学杂志 ›› 2008, Vol. 43 ›› Issue (01) : 1-4.

中国药学杂志 ›› 2008, Vol. 43 ›› Issue (01) : 1-4.
综述

心血管疾病治疗的新靶点——Rho激酶

  • 宫丽丽;方莲花;杜冠华
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摘要

目的阐述Rho激酶的发现、组织分布、生物学特点以及信号转导系统的结构功能及活性调节,探讨心血管疾病的发病过程中Rho激酶的作用机制及其抑制剂临床应用前景,为心血管疾病的防治提供新的药物作用靶点。方法依据近年国内外的相关文献对Rho激酶相关系统进行综述。结果与结论Rho/Rho激酶通过其介导的细胞信号传导系统影响平滑肌细胞的功能,通过与血管紧张素II、内皮素-1等血管活性物质相互作用,直接参与心血管疾病的发生。在分子水平,Rho激酶表达上调促进炎症、氧化应激、血栓形成和纤维化的各种因子,下调内皮型一氧化氮合酶。在细胞水平,Rho激酶介导血管平滑肌细胞收缩,促进增殖和迁移,促进炎细胞移动。

关键词

Rho激酶 / 心血管疾病 / 心肌梗死 / 心力衰竭 / 高血压 / 动脉粥样硬化

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宫丽丽;方莲花;杜冠华. 心血管疾病治疗的新靶点——Rho激酶[J]. 中国药学杂志, 2008, 43(01): 1-4

参考文献

[1]MATSUI T,AMANO M,YAMAMOTO T,et al. Rho-associated kinase,a novel serine/threonine kinase,as a putative target for the small GTP binding protein Rho[J]. EMBO J,1996,15(9): 2208-2216. [2]RIENTO K,RIDEY A J. Rocks: Multifunctional kinases in cell behaviour[J]. Nat Rev Mol Cell Bio,2003,4:446-456. [3]WIBBERLEY A,CHEN Z X,HU E,et al. Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle[J]. Br J Pharmacol,2003,138(5): 757 -766. [4]AMANO M,CHIHARA K,NAKAMURA N,et al. The COOH terminus of Rho-kinase negatively regulates Rho-kinase activity[J]. J Biol Chem,1999,274(45):32418-32424. [5]DORAN J D, LIU X, TASLIMI P,et al. New insights into the structure-function relationships of Rho-associated kinase: a thermodynamic and hydrodynamic study of the dimer-to-monomer transition and its kinetic implications[J]. Biochem J,2004,384:255-262. [6]COLEMAN M L,SAHAI E A,YEO M,et al. Membrane blebbing during apoptosis results from Caspase-mediated activation of ROCKI[J]. Nat Cell Biol,2001,3: 339-345. [7]BHADRIRAJU K,ELLIOTT J T,NGUYEN G,et al. Quantifying myosin light chain phosphorylation in single adherent cells with automated fluorescence microscopy[J]. BMC Cell Biology,2007,8:43. [8]HARTEL F V, RODEWALD C W, ASLAM M,et al. Extracellular ATP induces assembly and activation of the myosin light chain phosphatase complex in endothelial cells[J]. Cardiovasc Res,2007,74(3):487-496. [9]YAGITA Y, KITAGAWA K, SASAKI T,et al. Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia[J]. J Neurosci Res,2007,85(11):2460-2469. [10]UEHATA M,ISHIZAKI T,SATOH H,et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J]. Nature,1997,389:990-994. [11]CHRISSOBOLIS S,SOBEY C G. Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension Comparison with protein kinase C[J]. Circ Res,2001,88:774-779. [12]FARACI F M,LAMPING K G,MODRICK M L,et al. Cerebral vascular effects of angiotensin II: new insights from genetic models[J]. J Cerebr Blood F Met,2006,26(4):449-455. [13]ITO K,HIROOKA Y,KISHI T,et al. Rho/Rho-kinase pathway in the brainstem contributes to hypertension caused by chronic nitric oxide synthase inhibition[J]. Hypertension,2004,43:156-162. [14]LAUFS U,LIAO J K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase[J]. J Biol Chem,1998,273(37): 24266-24271. [15]WOLFRUM S,DENDORFER A,RIKITAKE Y,et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler[J]. Thromb Vasc Biol,2004,24(10):1842-1847. [16]DHVANIT I S, SINGH M. Effect of fasudil on macrovascular disorder-induced endothelial dysfunction[J]. Can J Physiol Pharmacol,2006,84(8-9): 835-845. [17]KOBAYASHI N,NAKANO S,MITA S I,et al. Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats[J]. J Pharmacol Exp Ther,2002,301(2):459-466. [18]SHIMOKAWA H,MORISHIGE K,MIYATA K,et al. Long-term inhibition of Rho-kinase induces a marked regression of arteriosclerotic coronary lesions in a porcine model in vivo[J]. Cardiovasc Res,2001,51(1):169-177. [19]MALLAT Z,GOJOVA A,SAUZEAU V,et al. Rho-associated protein kinase contributes to early atherosclerotic lesion formation in mice[J]. Circ Res,2003,93: 884-888. [20]SATO M,TANI E,FUJIKAWA H,et al. Involvement of Rho-kinase-mediated phosphorylation of myosin light chain in enhancement of cerebral vasospasm[J]. Circ Res,2000,87:195-200. [21]WATANABE Y,FARACI F M,HEISTAD D D,et al. Activation of Rho-associated kinase during augmented contraction of the basilar artery to serotonin after subarachnoid hemorrhage[J]. Am J Physiol,2005,288(6): 2653-2658. [22]WICKMAN G,LAN C,VOLLRATH B. Functional roles of the Rho/Rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin: relevance to subarachnoid hemorrhage and vasospasm[J]. Circ Res,2003,92:809-816. [23]LAN C, DAS D, WLOSKOWICZ A,et al. Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C[J]. Am J Physiol Heart Circ Physiol,2004,286(1):165-173. [24]KANDABASHI T,SHIMOKAWA H,MIYATA K,et al. Inhibition of myosin phosphatase by upregulated Rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1β[J]. Circulation,2000,101:1319-1323. [25]KANDABASHI T,SHIMOKAWA H,MIYATA K,et al. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm[J]. Arterioscl Throm Vas,2003,23:2209-2214. [26]HATTORI T,SHIMOKAWA H,HIGASHI M,et al. Long-term inhibition of Rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice[J]. Circulation,2004,109: 2234-2239. [27]QVIGSTAD E,SJAASTAD I,BRATTELID T,et al. Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart[J]. Circ Res,2005,97: 268-276. [28]HISAOKA T,YANO M,OHKUSA T,et al. Enhancement of Rho/Rho kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heat failure[J]. Cardiovasc Res,2001,49: 319-329.

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国家自然科学基金资助项目(30572182)

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