【Jpn Cir Res】molecular and cellular mechanisms of coronary artery spasm

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1、~f-1t::UALAI

2、Japanes巳population.B巳causecoronaryarteryspasmcanbeinducedbyavari巳tyofstimuliwithdifferentm巳chanismsofactíon,theoccurr巳nceofthespasmappearstobeduetothelocalhyperreactivityofthecoronaryarteryratherthantoanenhancedstimulationwithasinglemechanismofaction.Severallinesofevidenceindicatethatcoro

3、nary缸teryspasmiscausedprimarilybysmoothmusc1ehypercontractionwh巳reasthecontributionofendothelialdysfunctionmaybeminimal.Inordertoelucidat巳thec巳llularandmol巳cularmecha•nismsofthespasm,porcinemodelsofthespasmweredeveloped.Inth巳firstmodelwithballooninjuryandhigh-cholest巳rolfeeding,aclosetopo

4、logicalcorr巳latíonbetw巳巳nthe巳arlyath巳rosc1eroticlesionsandthespasticsiteswasnoted,whereasinthesecondmodelwithaninftammatorycytokineth巳potentíalimportanceofcoro•naryinf1ammatorychanges,especiallyattheadventitia,wasnot巳d.Subsequ巳ntstudiesinvivoandinvitrodemonstratedthatproteinkinaseC(PKC)an

5、dRho-kinas巳aresubstantiallyinvolvedintheintracellularmecha•nismofthespasm,resultinginincreasesinthemono-anddiphosphorylationsofmyosinlightchain(MLC).Furthermor巳，molecularbiologicalanalys巳sd巳monstratedthatRho-kinas巳isupr巳gulatedatthespasticsit，巳(atalllevels,inc1udingmRNA,protein,andactivit

6、y),resultingintheinhibitionofMLCphosphatasethroughthephos•phorylationofitsmyosinbindingsubunitandtherebycausingtheincreaseinMLCphosphorylations.Preliminaryresultsalsosuggestthatthelong-terminhibitíonofRho-kinas巳iseffectíveininhibitingth巳developmentofarteriosc1eroticvascularlesionsinsevera

7、lporcin巳models.Thus,Rho-kinas巳couldberegardedasanoveltherapeutictargetforcoronaryarteriosc1erosisingeneralandcoronaryarteryspasminparticular.(JpnCircJ2000;64:1-12)KeyWords:Coronaryarteryspasm;Myosinlightchain;Myosinphosphatase;ProteinkinaseC;Rho-kinase;Vascularsmoot