β-AR/PKA/CaMK Ⅱ信号通路在阿霉素诱导大鼠心肌细胞凋亡中的作用  

Roles of β-AR/PKA/CaMK Ⅱ signaling pathway in cardiomyocyte apoptosis induced by adriamycin in rats

作　　者：孙凤姣[1] 张译丹[1] 张密霞[1] 庄朋伟[1] 张艳军[1] 

机构地区：[1]天津中医药大学,天津市中药药理重点实验室,天津300193

出　　处：《中国药理学通报》2017年第3期360-365,共6页Chinese Pharmacological Bulletin

基　　金：国家重点基础研究发展计划(973计划)资助项目(No 2011CB505300,2011CB505302)

摘　　要：目的基于β肾上腺素受体信号通路探讨阿霉素诱导心衰发展过程中心肌细胞凋亡的分子生物学机制。方法SD大鼠70只,随机分为对照组(CON组,n=30)和阿霉素组(ADR组,n=40)。ADR组腹腔注射阿霉素,每次3 mg·kg^(-1),连续两周内每隔两天注射1次,共注射5次,累积总量为15 mg·kg^(-1)。于实验第2、4和6周分别观察实验大鼠一般状况和心功能,并取血清,ELISA法测定血清BNP和cTnT浓度。取心脏组织,HE、Masson和TUNEL染色观察病理形态学改变和凋亡,Western blot法检测β1-AR、β2-AR、PKA、CaMKⅡ等蛋白表达的变化。结果阿霉素注射完成后,ADR组EF和SV明显降低,血清BNP和cTn-T明显高于CON组,心脏明显萎缩,并伴随较轻心肌纤维化和凋亡,β1-AR、PKA、CaMKⅡ蛋白表达均降低。随着时间的延长,心脏收缩功能有所恢复,但BNP和cTn-T继续升高,心肌纤维化和凋亡严重,β1-AR表达进一步降低,β2-AR表达未见明显变化,PKA、CaMKⅡ表达逐渐升高。结论阿霉素诱导的心功能障碍、心肌重塑和凋亡动态改变过程可能与β-AR/PKA/Ca MKⅡ信号通路变化有关。Aim Toresearchthemolecularmecha-nisms of adriamycin-induced cardiomyocyte apoptosis based on β-adrenoceptor signaling pathway during de-velopmentofheartfailure.Methods SeventymaleSD rats were assigned randomly into two groups：the con-trol group（CON,n=30）and the ADR-induced cardio-toxicity group （ADR,n =40 ）.ADR was administered intraperitoneally in five equal injections （each contai-ning 3 mg·kg-1 ）over a period of two weeks,with a total cumulative dose of 15 mg · kg-1 body weight. Age-matched rats injected with saline were used as controls.The general condition of all rats was observed, and transthoracic echocardiography was performed im-mediately following the final ADR injection,and then every other week.Serum and myocardial tissue were harvested at W2,W4 and W6 separately.The serum contents of brain natriuretic peptide（BNP）and cardiac troponin-T（cTn-T）were analyzed by euzymelinked im-munosorbent assay （ELISA ）.The pathological change and apoptosis were determined by HE,Masson and ter-minal deoxyribonucleotide transferase-mediated dUTP nick end labeling （TUNEL）.The protein expressions ofβ1-AR,β2-AR,PKA and CaMK Ⅱ were detectedbyWesternblot.Results FollowingthefinalADRin-jection,cardiac systolic function and SV declined, which was accompanied by marked atrophy of the heart,low levels of cardiomyocyte fibrosis and apopto-sis,significantly increased serum BNP and cTn-T and decreased β1-AR,PKA and CaMK Ⅱ protein expres-sion.However,cardiac systolic function was improved with the extension of time but remained depressed as compared to CON group.The serum BNP and cTn-T concentration kept on rising.The gradual aggravation apoptosis and concomitant fibrosis in the ADR group heart were observed following ADR withdrawal.β1-AR protein expression was continuously down-regulated,β2-AR protein expression unchanged.Expression of PKA and CaMKⅡ proteins in hearts from ADR-injec-ted rats gradually increased.Conclusion β-AR/PKA/CaMKⅡ signaling pathway mediates cardiomyo-cyte apoptos

关 键 词：阿霉素 心脏毒性 Β肾上腺素受体 不同时期 心功能 凋亡 

分 类 号：R-332[医药卫生] R322.1