||心疾患におけるtitin, CaMKIIδおよびZASP/Cypher mRNAの選択的スプライシングの調節.
焦, 爽Jiao, Shuang
学位の種類: 博士（医学）. 報告番号: 甲第4269号. 学位記番号: 新大院博（医）甲第747号. 学位授与年月日: 平成29年3月23日
(0bjectives)Alternative splicing alters protein structure, localization and function and increases biological diversity in response to physiological and pathological stress conditions. We investigated how alternative splicing of titin, CaMKIIδ and ZASP/Cypher genes changes in hearts under pathologicalstress conditions. (Methods)The alternative splicing of titin, CaMKIIδ and ZASP/Cypher genes, in response to acute inflammation, pressure overload and hypoxia, was analyzed by quantitative RT-PCR in the hearts of experimental autoimmune myocarditis rats and myocarditis patients,monocrotaline pulmonaryhypertension rats and in cardiomyocytes cultured under hypoxic conditions.(Results) Large N2BA-titin, cytoplasmic CaMKIIδ and PGM1-binding ZASP/Cypher isoforms significantly increased in rat hearts with myocarditis and hypertrophy compared with normal hearts. Large N2BA-titin and cytoplasmic CaMKIIδ isoforms also significantly increased in myocarditis patient hearts compared with those with DCM. In cardiomyocytes under hypoxic conditions,PGM1-binding ZASP/Cypher isoforms significantly increased, but largeN2BA-titin and cytoplasmic CaMKIIδ isoforms decreased, compared with cells under normoxic conditions. (Conclusions) The alternative splicing of titin, CaMKIIδ and ZASP/Cypher genes was markedly modulated in hearts underpathological stress conditions and may be involved in adaptations to pathological changes.