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.
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Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/ threonine protein kinase activated by Cdc42 and Rac1. Nature 1994; 367(6458): 40–46
Manser E, Lim L. Roles of PAK family kinases. Prog Mol Subcell Biol 1999; 22: 115–133
Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci 2004; 117(19): 4343–4354
Zhao ZS, Manser E. PAK and other Rho-associated kinases—effectors with surprisingly diverse mechanisms of regulation. Biochem J 2005; 386(2): 201–214
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 Res 2007; 100(9): 1317–1327
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 Physiol 2009; 296(1): C47–C58
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 Cardiol 2013; 60: 121–128
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 Electrophysiol 2014, 7(5): 938–948
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 Cardiol 2014; 67: 77–85
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. Circulation 2011; 124(24): 2702–2715
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 Fail 2013; 6(4): 833–844
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 Cardiol 2011; 51(6): 988–996
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74(5): 1124–1136
Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 2008; 118(19): 1915–1919
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 Res 2007; 76(1): 41–50
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 Cardiol 2002; 34(5): 509–518
Egom EEA, Ke Y, Musa H, Mohamed TMA, Wang T, Cartwright E, Solaro RJ, Lei M. FTY720 prevents ischemia/reperfusion injuryassociated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. J Mol Cell Cardiol 2010; 48(2): 406–414
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 Res 2009; 83(2): 285–293
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 Physiol 2011; 301(4): H1487–H1495
Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 2006; 20(24): 3347–3365
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 Cardiol 2008; 44(2): 429–434
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 Physiol 2012; 302(1): H224–H230
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 Cardiol 2005; 39(3): 479–489
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Ke, Y., Wang, X., Jin, X.Y. et al. PAK1 is a novel cardiac protective signaling molecule. Front. Med. 8, 399–403 (2014). https://doi.org/10.1007/s11684-014-0380-9
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DOI: https://doi.org/10.1007/s11684-014-0380-9