Cardiology and Angiology I, Heart Center, Freiburg University, Hugstetter Str. 55, 79106, Freiburg, Germany.
Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, 901 19th Street South, BMR2 Rm 506, Birmingham, AL, 35294, USA.
Basic Res Cardiol. 2017 Dec 29;113(1):8. doi: 10.1007/s00395-017-0666-6. Print 2018 Jan 8.
Genetic factors are known to modulate cardiac susceptibility to ventricular hypertrophy and failure. To determine how strain influences the transcriptional response to pressure overload-induced heart failure (HF) and which of these changes accurately reflect the human disease, we analyzed the myocardial transcriptional profile of mouse strains with high (C57BL/6J) and low (129S1/SvImJ) susceptibility for HF development, which we compared to that of human failing hearts. Following transverse aortic constriction (TAC), C57BL/6J mice developed overt HF while 129S1/SvImJ did not. Despite a milder aortic constriction, impairment of ejection fraction and ventricular remodeling (dilation, fibrosis) was more pronounced in C57BL/6J mice. Similarly, changes in myocardial gene expression were more robust in C57BL/6J (461 genes) compared to 129S1/SvImJ mice (71 genes). When comparing these patterns to human dilated cardiomyopathy (1344 genes), C57BL/6J mice tightly grouped to human hearts. Overlay and bioinformatic analysis of the transcriptional profiles of C57BL/6J mice and human failing hearts identified six co-regulated genes (POSTN, CTGF, FN1, LOX, NOX4, TGFB2) with established link to HF development. Pathway enrichment analysis identified angiotensin and IGF-1 signaling as most enriched putative upstream regulator and pathway, respectively, shared between TAC-induced HF in C57BL/6J mice and in human failing hearts. TAC-induced heart failure in C57BL/6J mice more closely reflects the gene expression pattern of human dilated cardiomyopathy compared to 129S1/SvImJ mice. Unbiased as well as targeted gene expression and pathway analyses identified periostin, angiotensin signaling, and IGF-1 signaling as potential causes of increased HF susceptibility in C57BL/6J mice and as potentially useful drug targets for HF treatment.
遗传因素被认为可以调节心脏对心室肥大和衰竭的易感性。为了确定应变如何影响压力超负荷诱导的心力衰竭（HF）的转录反应，以及这些变化中哪些准确反映了人类疾病，我们分析了具有高（C57BL/6J）和低（129S1/SvImJ）HF 发展易感性的小鼠品系的心肌转录谱，我们将其与人类衰竭心脏进行了比较。在横主动脉缩窄（TAC）后，C57BL/6J 小鼠出现明显的 HF，而 129S1/SvImJ 则没有。尽管主动脉缩窄较轻，但 C57BL/6J 小鼠的射血分数和心室重构（扩张、纤维化）损伤更为明显。同样，C57BL/6J 小鼠（461 个基因）的心肌基因表达变化也比 129S1/SvImJ 小鼠（71 个基因）更为显著。当将这些模式与人类扩张型心肌病（1344 个基因）进行比较时，C57BL/6J 小鼠与人类心脏紧密聚集。C57BL/6J 小鼠和人类衰竭心脏转录谱的叠加和生物信息学分析确定了六个共同调节的基因（POSTN、CTGF、FN1、LOX、NOX4、TGFB2），这些基因与 HF 的发展有明确的联系。途径富集分析确定血管紧张素和 IGF-1 信号通路分别为 C57BL/6J 小鼠 TAC 诱导的 HF 和人类衰竭心脏中最丰富的潜在上游调节子和途径。C57BL/6J 小鼠 TAC 诱导的心力衰竭比 129S1/SvImJ 小鼠更能反映人类扩张型心肌病的基因表达模式。无偏和靶向基因表达和途径分析确定了骨桥蛋白、血管紧张素信号通路和 IGF-1 信号通路是 C57BL/6J 小鼠 HF 易感性增加的潜在原因，并且可能是 HF 治疗的有用药物靶点。
