吡格列酮对糖尿病兔心房重构的影响和机制研究  

Effects and mechanisms of pioglitazone on atrial remodeling in diabetic rabbits hearts

作　　者：刘长乐[1] 李广平[1] 富华颖[1] 李健[1] 程立君[1] 王兴华[1] 杨万松[1] 刘彤[1] 

机构地区：[1]天津医科大学第二医院心脏科天津心脏病学研究所,300211

出　　处：《中华心律失常学杂志》2013年第3期205-209,共5页Chinese Journal of Cardiac Arrhythmias

基　　金：国家自然科学基金（30900618）

摘　　要：目的建立四氧嘧啶介导的兔糖尿病（DM）模型，评价吡格列酮对DM兔心房结构性重构和电重构的干预作用及其可能机制。方法96只健康成年家兔分成正常对照组（CN组）、糖尿病组（DM组）、糖尿病＋吡格列酮A组（DPG组，4mg．kg^-1．d^-1）和糖尿病＋吡格列酮B组（DPI组，8mg．kg^-1．d^-1）。所有家兔均经超声心动图及血流动力学检测。建立Langendorff灌流的离体兔电生理心脏模型，测量房间传导时间（IACT）、心房有效不应期（AERP）及离散度（AERPD）并观察心房颤动（房颤）诱发率。病理学染色观察细胞形态，测定细胞直径及横截面积，天狼猩红染色测定心肌纤维化程度。Western-B lot检测观察组织纤维化指标ERK、pERK和TGF-B；观察炎症指标TLR4、NF—KBp50和TNF-仪等的蛋白表达特点。结果①基线超声心动图及血流动力学比较：DM组较CN组LAD、IVST和PWT明显增加，DPG和DPI组较DM组明显改善上述指标；DPI组SBP、DBP仅较DM组明显减低（P〈0．05）；②电生理参数比较：DM组较CN组心房各点AERP均不同程度延长，200ms刺激下HRA和LLA延长明显（P〈0．05）。DPG和DPI组较DM组显著降低IACT、AERPD，并减少房颤诱发率（P〈0．05）；③组织学比较：左心房组织HE染色和天狼猩红染色显示DM组左心房肌间质纤维组织增生明显，心肌细胞直径、横截面积较CN组均明显增加。DPG和DPI组上述病理变化明显减轻（P〈0．05）；④分子生物学比较：DM组较CN组明显上调pERK、TGF．B、TLR4、NF-KBp50和TNF-α的蛋白表达水平，DPG和DPI组较DM组下调上述指标蛋白表达水平。结论吡格列酮限制了DM对心房电重构和结构重构的发生和进展，并有潜在的逆转作用使房颤不易诱发。Objective To investigate the underlying mechanisms caused by pioglitazone on atrial structural remodeling and electrical remodeling in alloxan-induced diabetic rabbits. Methods Ninety-six rabbits were divided into control （CN） group, diabetes mellitus （DM） group, diabetes mellitus ＋ pioglitazone （DPG） group and diabetes mellitus ＋ double pioglitazone （DPI） group. Isolated Langendorff-perfused rabbit hearts were used to measure electrophysiological parameters and vulnerability to atrial fibrillation （AF）.Histopathologic examinations were performed to identify the fibrosis in left atria. Western-Blot was applied to as- sess protein expressions of extracellular signal-regulated kinase （ERK） , phosphorylation ERK （pERK） , transforming growth factor-α （TGFI3） ,toll-like receptor 4 （TLR4） ,nuclear factor-KB p50 （ NF-KB p50） and tumor necrosis factorr （TNF-ot）. Results①Left atrium diameter （ LAD）, interventricular septum （IVST） and posterior wall thickness （PWT）were significantly increased＇in DM group compared with controls, which were markedly reduced by pioglitazone.Systolic blood pressure （SBP）and diastolic blood pressure （DBP）in DPI group were significantly lower than that in DM group （P〈0. 05）.②Inter-atrial conduction time （IACT） and atrial effective refractory period dispersion （AERPD）were prolonged and AF inducibility was increased in DM group （P〈0.05）compared with controls, which were markedly reduced by pioglitazone.③Pioglitazone attenua- ted atrial structural remodeling, with significant reductions in CVF.④Western-blot analysis revealed that DM increased protein expressions of pERK, TGF-α, TLR4, NF-kB p50 and TNF-α, which were reduced by pioglitazone. Conclusion Pioglitazone inhibited atrial structural remodeling and electrical remodeling in diabetic rabbits, resulting in decreased inducibility of DM-related AF.

关 键 词：心房颤动 糖尿病 吡格列酮 电重构 结构重构 

分 类 号：R587[医药卫生—内分泌]