AKT network of genes and impaired myocardial contractility during murine acute chagasic myocarditis

Rationale: Chagasic disease is associated with high morbidity in Latin America. Acute Chagasic myocarditis is consistently found in acute infections but little is known about its contribution to chronic cardiomyopathy. The aim of the study was to phenotypically characterize two strains of mice with differential Chagas infection susceptibility and correlate strain myocarditis phenotypes with heart tissue gene expression. Methods: C57BL/6J and Balb/c mice were injected intraperitoneally with 0 or 150-200 tissue-derived trypomastigotes (Tulahuen strain). Echocardiograms, brain natriuretic peptide and troponin were measured. Heart tissue was harvested for histopathological analysis and gene expression profiling on microarrays. Genes differently expressed between infected Balb/c and C57BL/6J were identified Results: Echocardiograms demonstrated differences in heart rate in Balb/c vs. C57BL/6J infected mice: 413 vs. 476 bpm, (p=0.0001), stroke volume: 31.9 ± 9.3 vs. 39.2 ± 5.5 µl (p=0.03); and cardiac output: 13.1 ± 3.5 vs. 18.7 ± 3.2 µl/min (p=0.002). Gene expression at 4 weeks analysis demonstrated 32 statistically significant (q-value < 0.05) differentially expressed genes between infected Balb/c and C57BL/6J which were enriched for genes related to protein kinase B (AKT) pathway 8 Balb/c mice and 8 C57BL/6J mice were infected and 8 Balb/c and 8 C57BL/6J were used as controls. 6 mice per group were used for gene expression analysis.研究背景：恰加斯病（Chagasic disease）在拉丁美洲地区具有较高的发病率。急性恰加斯性心肌炎在急性感染阶段始终可被检出，但目前对其在慢性心肌病发生发展中的作用尚不清楚。本研究旨在对两种对恰加斯病感染易感性存在差异的小鼠品系进行表型表征，并将不同品系的心肌炎表型与心脏组织基因表达水平进行关联分析。 方法：将C57BL/6J与Balb/c小鼠分别腹腔注射0或150~200个组织来源的锥鞭毛体（trypomastigotes）图拉亨株（Tulahuen strain）。对小鼠开展超声心动图（echocardiograms）检测、脑钠肽（brain natriuretic peptide）与肌钙蛋白（troponin）水平测定。采集心脏组织用于组织病理学分析及微阵列（microarrays）基因表达谱检测，并鉴定感染的Balb/c与C57BL/6J小鼠之间的差异表达基因。 结果：超声心动图检测结果显示，感染后的Balb/c与C57BL/6J小鼠存在多项心脏功能指标差异：心率分别为413与476次/分钟（bpm）（p=0.0001）；每搏输出量分别为31.9 ± 9.3与39.2 ± 5.5 µl（p=0.03）；心输出量分别为13.1 ± 3.5与18.7 ± 3.2 µl/min（p=0.002）。感染后4周的基因表达分析显示，感染的Balb/c与C57BL/6J小鼠之间存在32个具有统计学意义（q值<0.05）的差异表达基因，这些基因显著富集于蛋白激酶B（AKT）通路。本研究共纳入8只感染组Balb/c小鼠、8只感染组C57BL/6J小鼠，同时设置8只Balb/c对照组小鼠与8只C57BL/6J对照组小鼠，每组选取6只小鼠用于基因表达分析。