β受体-PKA-AKAP信号通路调控心力衰竭的研究进展

doi:10.12092/j.issn.1009-2501.2018.05.018

摘要/Abstract

摘要：

心力衰竭是各种心血管疾病发展的终末阶段，其死亡率高，预后差，是危害人类生命健康的重大疾病。心力衰竭时，交感神经系统激活，儿茶酚胺激活β受体（β-AR）通过Gs蛋白-腺苷酸环化酶-环磷酸腺苷-蛋白激酶A（Gs-AC-cAMP-PKA）信号通路增加心输出量，这在短期内有益，但持续激活β受体最终会导致心脏收缩力降低。在这一病理过程中，A型激酶锚定蛋白（AKAP）起着重要的作用，AKAP通过将PKA锚定在特定的亚细胞区域来调节信号通路。β受体阻滞剂被广泛用于心力衰竭的治疗，但也会带来一系列的副作用。因此，未来需要更加新颖且有针对性的治疗方法来改善心衰。

关键词: A型激酶锚定蛋白, 心力衰竭, 蛋白激酶A, β肾上腺素能受体

Abstract:

Heart failure is the final stage of the development of various cardiovascular diseases. Because of its high mortality rate and poor prognosis, it has become a major disease that endangers human life and health. In heart failure, the sympathetic system is activated and the catecholamines stimulate β-adrenergic receptor (β-AR) to increase cardiac output via Gs-AC-cAMP-PKA signaling pathway, which is beneficial in the acute phase, but chronic β-ARs stimulation eventually leads to a diminished contractile performance of the heart. A-kinase anchoring protein (AKAP) plays an important role in this pathological process, which regulates signaling pathways by anchoring PKA in specific subcellular locations. β-blockers are widely used in the treatment of heart failure, but also have a range of side effects.Therefore, novel and more targeted therapeutic treatments are needed to improve treatment of HF in the future.

Key words: kinase anchoring protein, heart failure, protein kinase A, β-adrenergic receptor

中图分类号:

R541.6

黄霆，汪和贵. β受体-PKA-AKAP信号通路调控心力衰竭的研究进展[J]. 中国临床药理学与治疗学, 2018, 23(5): 592-596.

HUANG Ting, WANG Hegui. Research progress in regulation of heart failure by β-adrenergic-receptor-PKA-AKAP signaling pathway[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(5): 592-596.

参考文献

［1］Bers DM. Cardiac excitation-contraction coupling［J］. Nature, 2002,415(6868):198-205.
［2］Baker AJ. Adrenergic signaling in heart failure: a balance of toxic and protective effects［J］. Pflugers Arch, 2014,466(6):1139-1150.
［3］Vassilatis DK, Hohmann JG, Zeng H, et al. The G protein-coupled receptor repertoires of human and mouse［J］. Proc Natl Acad Sci U S A, 2003,100(8):4903-4908.
［4］Cannavo A, Liccardo D, Koch WJ. Targeting cardiac beta-adrenergic signaling via GRK2 inhibition for heart failure therapy［J］. Front Physiol, 2013,4:264.
［5］Moniotte S, Kobzik L, Feron O, et al. Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium［J］. Circulation, 2001,103(12):1649-1655.
［6］Xiang Y, Kobilka BK. Myocyte adrenoceptor signaling pathways.［J］. Science (New York, N.Y.), 2003,300(5625):1530-1532.
［7］Kuster DW, Bawazeer AC, Zaremba R, et al. Cardiac myosin binding protein C phosphorylation in cardiac disease［J］. J Muscle Res Cell Motil, 2012,33(1):43-52.
［8］Stelzer JE, Patel JR, Walker JW, et al. Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation［J］. Circ Res, 2007,101(5):503-511.
［9］Yamasaki R, Wu Y, McNabb M, et al. Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes［J］. Circ Res, 2002,90(11):1181-1188.
［10］Ginsburg KS, Bers DM. Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger［J］. J Physiol, 2004,556(Pt 2):463-480.
［11］van der Heyden MA,Wijnhoven TJ,Opthof T.Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels［J］.Cardiovasc Res,2005,65(1):28-39.
［12］Ruehr ML, Russell MA, Bond M. A-kinase anchoring protein targeting of protein kinase A in the heart［J］. J Mol Cell Cardiol, 2004,37(3):653-665.
［13］Diviani D, Maric D, Perez LI, et al. A-kinase anchoring proteins: molecular regulators of the cardiac stress response［J］. Biochim Biophys Acta, 2013,1833(4):901-908.
［14］Skroblin P, Grossmann S, Schafer G, et al. Mechanisms of protein kinase A anchoring［J］. Int Rev Cell Mol Biol, 2010,283:235-330.
［15］Di Benedetto G, Zoccarato A, Lissandron V, et al. Protein kinase A type I and type II define distinct intracellular signaling compartments［J］. Circ Res, 2008,103(8):836-844.
［16］Barradeau S, Imaizumi-Scherrer T, Weiss MC, et al. Intracellular targeting of the type-I alpha regulatory subunit of cAMP-dependent protein kinase［J］. Trends Cardiovasc Med, 2002,12(6):235-241.
［17］Xiang YK. Compartmentalization of beta-adrenergic signals in cardiomyocytes［J］. Circ Res, 2011,109(2):231-244.
［18］Stangherlin A, Gesellchen F, Zoccarato A, et al. cGMP signals modulate cAMP levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac myocytes［J］. Circ Res, 2011,108(8):929-939.
［19］Bers DM, Ziolo MT. When is cAMP not cAMP? Effects of compartmentalization［J］. Circ Res, 2001,89(5):373-375.
［20］Lygren B, Carlson CR, Santamaria K, et al. AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum［J］. EMBO Rep, 2007,8(11):1061-1067.
［21］Sumandea CA, GarciaCazarin ML, Bozio CH, et al. Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments［J］. J Biol Chem, 2011,286(1):530-541.
［22］Uys GM, Ramburan A, Loos B, et al. Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C［J］. BMC Cell Biol, 2011,12:18.
［23］Hundsrucker C, Klussmann E. Direct AKAP-mediated protein-protein interactions as potential drug targets［J］. Handb Exp Pharmacol, 2008(186):483-503.
［24］Ryall JG, Schertzer JD, Murphy KT, et al. Chronic beta2-adrenoceptor stimulation impairs cardiac relaxation via reduced SR Ca2+-ATPase protein and activity［J］. Am J Physiol Heart Circ Physiol, 2008,294(6):H2587-H2595.
［25］Dessauer CW. Adenylyl cyclase-A-kinase anchoring protein complexes: the next dimension in cAMP signaling［J］. Mol Pharmacol, 2009,76(5):935-941.
［26］McMurray JJ, Adamopoulos S, Anker S D, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC［J］. Eur Heart J, 2012,33(14):1787-1847.
［27］Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis［J］. Ann Intern Med, 2001,134(7):550-560.
［28］Teerlink JR, Massie BM. The role of beta-blockers in preventing sudden death in heart failure［J］. J Card Fail, 2000,6(2 Suppl 1):25-33.
［29］Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis［J］. CMAJ, 2006,174(12):1737-1742.
［30］Messerli FH, Beevers DG, Franklin SS, et al. beta-Blockers in hypertension-the emperor has no clothes: an open letter to present and prospective drafters of new guidelines for the treatment of hypertension［J］. Am J Hypertens, 2003,16(10):870-873.
［31］Liang M, Puri A, Devlin G. Heart rate and cardiovascular disease: an alternative to Beta blockers［J］. Cardiol Res Pract, 2009,2009:179350.
［32］Malik FI, Hartman JJ, Elias KA, et al. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure［J］. Science, 2011,331(6023):1439-1443.
［33］Orstavik O, Ata SH, Riise J, et al. Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart［J］. Br J Pharmacol, 2014,171(23):5169-5181.
［34］Mebazaa A, Barraud D, Welschbillig S. Randomized clinical trials with levosimendan［J］. Am J Cardiol, 2005,96(6A):74G-79G.
［35］Passino C, Severino S, Poletti R, et al. Aerobic training decreases B-type natriuretic peptide expression and adrenergic activation in patients with heart failure［J］. J Am Coll Cardiol, 2006,47(9):1835-1839.
［36］Lavie CJ, Arena R, Swift DL, et al. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes［J］. Circ Res, 2015,117(2):207-219.
［37］Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines［J］. J Am Coll Cardiol, 2013,62(16):e147-e239.
［38］McConnell BK, Popovic Z, Mal N, et al. Disruption of protein kinase A interaction with A-kinase-anchoring proteins in the heart in vivo: effects on cardiac contractility, protein kinase A phosphorylation, and troponin I proteolysis［J］. J Biol Chem, 2009,284(3):1583-1592.

[1]	郝潇, 赵美, 王文静, 张飞飞, 刘惠良, 党懿, 李树仁, 齐晓勇. 钠-葡萄糖共转运体2抑制剂在急性心肌梗死应用研究进展[J]. 中国临床药理学与治疗学, 2023, 28(7): 824-831.
[2]	彭勇, 范剑峰, 熊旭华, 肖冬平, 高招波, 郑春华. 右旋糖酐铁片对合并铁缺乏的射血分数减低的心力衰竭患者的影响[J]. 中国临床药理学与治疗学, 2023, 28(2): 178-183.
[3]	陈玉林, 蒋虎刚, 王新强, 刘凯, 李应东, 安涛, 赵信科. 基于网络药理学和分子对接探讨芪参益心颗粒治疗射血分数保留型心力衰竭的作用机制[J]. 中国临床药理学与治疗学, 2023, 28(10): 1081-1092.
[4]	杨胜, 王德国. 沙库巴曲缬沙坦联合达格列净治疗射血分数减低型心力衰竭疗效及对血清cTnⅠ、BNP水平的影响[J]. 中国临床药理学与治疗学, 2022, 27(9): 1010-1015.
[5]	彭娟, 范琳琳, 李然宜, 李晓宇, 吕迁洲, 邹云增. 心力衰竭药物治疗的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(4): 373-381.
[6]	刘平, 邱博, 吴惠珍. 维利西呱治疗心力衰竭的药理作用与临床评价[J]. 中国临床药理学与治疗学, 2022, 27(2): 212-218.
[7]	徐永华, 施向红. 托拉塞米联合左卡尼汀治疗慢性心力衰竭的疗效分析[J]. 中国临床药理学与治疗学, 2021, 26(6): 647-652.
[8]	陈力方, 王博, 王维蓉. 组蛋白去乙酰化酶3在心血管疾病中的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(1): 88-97.
[9]	范剑峰，方译，郑春华. 沙库巴曲缬沙坦钠治疗慢性心力衰竭患者的临床疗效分析[J]. 中国临床药理学与治疗学, 2019, 24(7): 810-814.
[10]	沈蕾，王柯柯，杨景柯，赵俊涛，孟祥光，袁义强. 心力衰竭治疗药物的表观遗传药理学进展[J]. 中国临床药理学与治疗学, 2019, 24(3): 343-349.
[11]	魏子寒，李栋博，元峥，陆颍，杨国杰. 沙库巴曲缬沙坦治疗左心疾病相关性肺动脉高压的临床研究[J]. 中国临床药理学与治疗学, 2019, 24(1): 57-62.
[12]	王世彪，王程毅，翁斌，郭晓峰，林海. 无创心输出量监测联合米力农在小儿重症肺炎并心力衰竭中的疗效对比观察及对脑钠肽水平的影响研究[J]. 中国临床药理学与治疗学, 2018, 23(12): 1402-1407.
[13]	刘玉，张颖，王安才. 重组人脑利钠肽对慢性收缩性心力衰竭合并利尿剂抵抗患者的疗效及对TNF-α、NPY的影响[J]. 中国临床药理学与治疗学, 2017, 22(7): 814-820.
[14]	伍长娟，汤天生. 振源胶囊辅助治疗慢性心力衰竭疗效及安全性的Meta分析[J]. 中国临床药理学与治疗学, 2017, 22(3): 299-304.
[15]	刘长江，武洋，邵培培，李少华，程路峰. 游泳力竭对冠脉结扎致大鼠慢性心衰模型的优化[J]. 中国临床药理学与治疗学, 2017, 22(12): 1340-1345.