Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (4) : 399-403    https://doi.org/10.1007/s11684-014-0380-9
MINI-REVIEW
PAK1 is a novel cardiac protective signaling molecule
Yunbo Ke1,Xin Wang2,Xu Yu Jin3,R. John Solaro1,Ming Lei4,*()
1. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA
2. Faculty of Life Science, University of Manchester, Manchester M13 9NT, UK
3. Department of Cardiothoracic Surgery, John Radcliffe Hospital; Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
4. Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK
 Download: PDF(185 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates. We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca2+ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.

Keywords p21-activated kinase 1 (PAK1)      heart     
Corresponding Author(s): Ming Lei   
Just Accepted Date: 24 October 2014   Online First Date: 24 November 2014    Issue Date: 18 December 2014
 Cite this article:   
Yunbo Ke,Xin Wang,Xu Yu Jin, et al. PAK1 is a novel cardiac protective signaling molecule[J]. Front. Med., 2014, 8(4): 399-403.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0380-9
https://academic.hep.com.cn/fmd/EN/Y2014/V8/I4/399
Fig.1  PAK1 provides a novel target for developing target-based therapies for cardiac adrenergic and hypertrophic stress conditions through its multiple cardiac protective effects via transcriptional mechanisms and post-transcriptional mechanisms (regulating eNOS and PP2A).
1 Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature1994; 367(6458): 40-46
https://doi.org/10.1038/367040a0 pmid: 8107774
2 Manser E, Lim L. Roles of PAK family kinases. Prog Mol Subcell Biol1999; 22: 115-133
https://doi.org/10.1007/978-3-642-58591-3_6 pmid: 10081067
3 Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci2004; 117(19): 4343-4354
https://doi.org/10.1242/jcs.01392 pmid: 15331659
4 Zhao ZS, Manser E. PAK and other Rho-associated kinases—effectors with surprisingly diverse mechanisms of regulation. Biochem J2005; 386(2): 201-214
https://doi.org/10.1042/BJ20041638 pmid: 15548136
5 Ke Y, Lei M, Collins TP, Rakovic S, Mattick PAD, Yamasaki M, Brodie MS, Terrar DA, Solaro RJ. Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells. Circ Res2007; 100(9): 1317-1327
https://doi.org/10.1161/01.RES.0000266742.51389.a4 pmid: 17413045
6 Sheehan KA, Ke Y, Wolska BM, Solaro RJ. Expression of active p21-activated kinase-1 induces Ca2+ flux modification with altered regulatory protein phosphorylation in cardiac myocytes. Am J Physiol Cell Physiol2009; 296(1): C47-C58
https://doi.org/10.1152/ajpcell.00012.2008 pmid: 18923061
7 DeSantiago J, Bare DJ, Ke Y, Sheehan KA, Solaro RJ, Banach K. Functional integrity of the T-tubular system in cardiomyocytes depends on p21-activated kinase 1. J Mol Cell Cardiol2013; 60: 121-128
https://doi.org/10.1016/j.yjmcc.2013.04.014 pmid: 23612118
8 Wang Y, Tsui H, Ke Y, Shi Y, Li Y, Davies L, Cartwright EJ, Venetucci L, Zhang H, Terrar DA, Huang CLH, Solaro RJ, Wang X, Lei M. Pak1 is required to maintain ventricular ca2+ homeostasis and electrophysiological stability through serca2a regulation in mice. Circ Arrhythm Electrophysiol2014<month>Sep</month><day>12</day>[Epub ahead of print]
https://doi.org/10.1161/CIRCEP.113.001198 pmid: 25217043
9 DeSantiago J, Bare DJ, Xiao L, Ke Y, Solaro RJ, Banach K. p21-Activated kinase1 (Pak1) is a negative regulator of NADPH-oxidase 2 in ventricular myocytes. J Mol Cell Cardiol2014; 67: 77-85
https://doi.org/10.1016/j.yjmcc.2013.12.017 pmid: 24380729
10 Liu W, Zi M, Naumann R, Ulm S, Jin J, Taglieri DM, Prehar S, Gui J, Tsui H, Xiao RP, Neyses L, Solaro RJ, Ke Y, Cartwright EJ, Lei M, Wang X. Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Circulation2011; 124(24): 2702-2715
https://doi.org/10.1161/CIRCULATIONAHA.111.048785 pmid: 22082674
11 Liu W, Zi M, Tsui H, Chowdhury SK, Zeef L, Meng QJ, Travis M, Prehar S, Berry A, Hanley NA, Neyses L, Xiao RP, Oceandy D, Ke Y, Solaro RJ, Cartwright EJ, Lei M, Wang X. A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin. Circ Heart Fail2013; 6(4): 833-844
https://doi.org/10.1161/CIRCHEARTFAILURE.112.000123 pmid: 23753531
12 Taglieri DM, Monasky MM, Knezevic I, Sheehan KA, Lei M, Wang X, Chernoff J, Wolska BM, Ke Y, Solaro RJ. Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A. J Mol Cell Cardiol2011; 51(6): 988-996
https://doi.org/10.1016/j.yjmcc.2011.09.016 pmid: 21971074
13 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation1986; 74(5): 1124-1136
https://doi.org/10.1161/01.CIR.74.5.1124 pmid: 3769170
14 Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation2008; 118(19): 1915-1919
https://doi.org/10.1161/CIRCULATIONAHA.108.805242 pmid: 18981312
15 Jin ZQ, Zhang J, Huang Y, Hoover HE, Vessey DA, Karliner JS. A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury. Cardiovasc Res2007; 76(1): 41-50
https://doi.org/10.1016/j.cardiores.2007.05.029 pmid: 17610857
16 Lecour S, Smith RM, Woodward B, Opie LH, Rochette L, Sack MN. Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol2002; 34(5): 509-518
https://doi.org/10.1006/jmcc.2002.1533 pmid: 12056855
17 Egom EEA, Ke Y, Musa H, Mohamed TMA, Wang T, Cartwright E, Solaro RJ, Lei M. FTY720 prevents ischemia/reperfusion injury-associated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. J Mol Cell Cardiol2010; 48(2): 406-414
https://doi.org/10.1016/j.yjmcc.2009.10.009 pmid: 19852968
18 Hofmann U, Burkard N, Vogt C, Thoma A, Frantz S, Ertl G, Ritter O, Bonz A. Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia-reperfusion. Cardiovasc Res2009; 83(2): 285-293
https://doi.org/10.1093/cvr/cvp137 pmid: 19416991
19 Egom EEA, Mohamed TMA, Mamas MA, Shi Y, Liu W, Chirico D, Stringer SE, Ke Y, Shaheen M, Wang T, Chacko S, Wang X, Solaro RJ, Fath-Ordoubadi F, Cartwright EJ, Lei M. Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury. Am J Physiol Heart Circ Physiol2011; 301(4): H1487-H1495
https://doi.org/10.1152/ajpheart.01003.2010 pmid: 21705677
20 Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev2006; 20(24): 3347-3365
https://doi.org/10.1101/gad.1492806 pmid: 17182864
21 Mao K, Kobayashi S, Jaffer ZM, Huang Y, Volden P, Chernoff J, Liang Q. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. J Mol Cell Cardiol2008; 44(2): 429-434
https://doi.org/10.1016/j.yjmcc.2007.10.016 pmid: 18054038
22 Monasky MM, Taglieri DM, Patel BG, Chernoff J, Wolska BM, Ke Y, Solaro RJ. p21-activated kinase improves cardiac contractility during ischemia-reperfusion concomitant with changes in troponin-T and myosin light chain 2 phosphorylation. Am J Physiol Heart Circ Physiol2012; 302(1): H224-H230
https://doi.org/10.1152/ajpheart.00612.2011 pmid: 22037191
23 Nelson TJ, Balza R Jr, Xiao Q, Misra RP. SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy. J Mol Cell Cardiol2005; 39(3): 479-489
https://doi.org/10.1016/j.yjmcc.2005.05.004 pmid: 15950986
[1] Jing Ma, Shiyu Chen, Lili Hao, Wei Sheng, Weicheng Chen, Xiaojing Ma, Bowen Zhang, Duan Ma, Guoying Huang. Long non-coding RNA SAP30-2:1 is downregulated in congenital heart disease and regulates cell proliferation by targeting HAND2[J]. Front. Med., 2021, 15(1): 91-100.
[2] Hui Wang, Yang Zhang, Zhujun Shen, Ligang Fang, Zhenyu Liu, Shuyang Zhang. Prognostic value of fasting glucose on the risk of heart failure and left ventricular systolic dysfunction in non-diabetic patients with ST-segment elevation myocardial infarction[J]. Front. Med., 2021, 15(1): 70-78.
[3] Yufeng Zhao, Xueyun Yu, Xinyu Cao, Lin Luo, Liyun He, Shusong Mao, Li Ma, Peijing Rong, Yuxue Zhao, Guozheng Li, Baoyan Liu. Cluster analysis for syndromes of real-world coronary heart disease with angina pectoris[J]. Front. Med., 2018, 12(5): 566-571.
[4] Hongli Yin,Tianyi Liu,Ying Zhang,Baofeng Yang. Caveolin proteins: a molecular insight into disease[J]. Front. Med., 2016, 10(4): 397-404.
[5] Qingqiang Ni,Lin Yun,Rui Xu,Guohua Li,Yucai Yao,Jiamin Li. A rare chronic constrictive pericarditis with localized adherent visceral pericardium and normal parietal pericardium: a case report[J]. Front. Med., 2016, 10(3): 356-359.
[6] Ripen NSENGA MD, Longxian CHENG PhD, Mei’an HE PhD, Tangchun WU PhD, . The role of natriuretic peptide precursor A gene polymorphism in the development of coronary heart disease in Chinese Han population?[J]. Front. Med., 2009, 3(4): 437-442.
[7] CAI Chunquan, ZHANG Qingjiang, SHEN Changhong. Vein of Galen malformations - report of 2 cases and literature review[J]. Front. Med., 2008, 2(3): 317-322.
[8] DONG Nianguo, SHI Jiawei, CHEN Si, HONG Hao, HU Ping. Current progress on scaffolds of tissue engineering heart valves[J]. Front. Med., 2008, 2(3): 229-234.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed