《p21活化蛋白激酶与心血管疾病：从病理生理学到药物发现》.pdf

· 476 · 中国药理学与毒理学杂志2014年 8月第28卷第4期 ChinJPharmacolToxicol，Vol28，No4，Aug2014 beendisappointingincludingtrialsofTNFa antag- functions．Thus，thesestudiessuggestthatPakl onists，anti-oxidantsand an activatorofsoluble is more important in the heart than previously guanylatecyclasewhichactsasavasodilator．1tis thought．inparticularitscardiacprotectiveeffects alsoevidentthattheuseofstem celItherapiesfor andtherapeuticpotentia1．Thisreview lsaimedto heartfailure is notsolution to the problem．ItIs giveanoverview offunctionofPaklintheheart clearfr0m trialsthatstem cells did notintegrate andanew therapeuticoptionformanagementof anddifferentiate inot cardiaccellswheninjected heartdiseaserisingfr0m Paklactivation． intothe myocardium．However．itisvaluable to notethatsomestudieshaveshownthatstem cells 1 Structureand activation mechanism mightexertabeneficiaryeffectinheartfailurepa— ofPakl tientsthroughsecretionofsomeparacrinefactors． Therefore。discovery ofnew geneswhichmod— Pakl，alsoknownasPakcz，isexpresseddi— ulate heartfailure is essentia1．Targeting ofthese verselyina rangeoftissues．Invivoand n／ vitro genes with pharmacologicaIregulators to provide experimentshave iIlustratedthattheN-terminaIof safeandinexpensivetherapiesremainsaviableaim PaklexhibitinhibitoryfunctionaswelIasposses- forthetreatmentofheartfailureinthefuture． singtheabilitytobindp21(Fig．1)12J．Thebind— Protein kinasesareversatile signaling mole— ing0fGTPboundRacl(GTP·Rac1)relieson culesthatare involved in the regulation ofmost the charge ofthe polybasicdomainupstream of physiologicalresponses in biologicalsystems in theCdc42／Raclinteractionbinding(CRIB)do— theheart．Thep21一activatedkinases(Paks)are main (Iysine66—68)：with no effectonGTP- groupofserine／threonineproteinkinasesthatare Cdc42binding．Paklactivation issignificantlyre· activatedbyCdc42 and Raclandwerefirstdis- ducedwith the replaceme