Rodrigues Patrícia G, Miranda-Silva Daniela, Li Xidan, Sousa-Mendes Cláudia, Martins-Ferreira Ricardo, Elbeck Zaher, Leite-Moreira Adelino F, Knöll Ralph, Falcão-Pires Inês
Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal.
Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Heart and Vascular Theme, Karolinska Institutet, 171 77 Stockholm, Sweden.
Int J Mol Sci. 2020 Dec 18;21(24):9687. doi: 10.3390/ijms21249687.
This study aims to provide new insights into transcriptome and miRome modifications occurring in cardiac reverse remodelling (RR) upon left ventricle pressure-overload relief in mice. Pressure-overload was established in seven-week-old C57BL/6J-mice by ascending aortic constriction. A debanding (DEB) surgery was performed seven weeks later in half of the banding group (BA). Two weeks later, cardiac function was evaluated through hemodynamics and echocardiography, and the hearts were collected for histology and small/bulk-RNA-sequencing. Pressure-overload relief was confirmed by the normalization of left-ventricle-end-systolic-pressure. DEB animals were separated into two subgroups according to the extent of cardiac remodelling at seven weeks and RR: DEB1 showed an incomplete RR phenotype confirmed by diastolic dysfunction persistence (E/e' ≥ 16 ms) and increased myocardial fibrosis. At the same time, DEB2 exhibited normal diastolic function and fibrosis, presenting a phenotype closer to myocardial recovery. Nevertheless, both subgroups showed the persistence of cardiomyocytes hypertrophy. Notably, the DEB1 subgroup presented a more severe diastolic dysfunction at the moment of debanding than the DEB2, suggesting a different degree of cardiac remodelling. Transcriptomic and miRomic data, as well as their integrated analysis, revealed significant downregulation in metabolic and hypertrophic related pathways in DEB1 when compared to DEB2 group, including fatty acid β-oxidation, mitochondria L-carnitine shuttle, and nuclear factor of activated T-cells pathways. Moreover, extracellular matrix remodelling, glycan metabolism and inflammation-related pathways were up-regulated in DEB1. The presence of a more severe diastolic dysfunction at the moment of pressure overload-relief on top of cardiac hypertrophy was associated with an incomplete RR. Our transcriptomic approach suggests that a cardiac inflammation, fibrosis, and metabolic-related gene expression dysregulation underlies diastolic dysfunction persistence after pressure-overload relief, despite left ventricular mass regression, as echocardiographically confirmed.
本研究旨在深入了解小鼠左心室压力超负荷解除后心脏逆向重塑（RR）过程中发生的转录组和微小RNA组修饰。通过升主动脉缩窄在7周龄的C57BL/6J小鼠中建立压力超负荷模型。7周后，对一半的缩窄组（BA）小鼠进行解除缩窄（DEB）手术。两周后，通过血流动力学和超声心动图评估心脏功能，并收集心脏进行组织学检查和小/大RNA测序。左心室收缩末期压力恢复正常证实了压力超负荷的解除。根据7周时心脏重塑程度和RR情况，将DEB动物分为两个亚组：DEB1表现出不完全RR表型，舒张功能障碍持续存在（E/e'≥16 ms）且心肌纤维化增加。同时，DEB2表现出正常的舒张功能和纤维化，呈现出更接近心肌恢复的表型。然而，两个亚组均显示心肌细胞肥大持续存在。值得注意的是，DEB1亚组在解除缩窄时的舒张功能障碍比DEB2更严重，提示心脏重塑程度不同。转录组和微小RNA组数据及其综合分析显示，与DEB2组相比，DEB1中代谢和肥厚相关途径显著下调，包括脂肪酸β氧化、线粒体L-肉碱穿梭和活化T细胞核因子途径。此外，DEB1中细胞外基质重塑、聚糖代谢和炎症相关途径上调。在心脏肥大基础上，压力超负荷解除时更严重的舒张功能障碍与不完全RR相关。我们的转录组学方法表明，尽管超声心动图证实左心室质量有所恢复，但压力超负荷解除后舒张功能障碍持续存在的基础是心脏炎症、纤维化和代谢相关基因表达失调。
