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Differential microRNA-21 and microRNA-221 Upregulation in the Biventricular Failing Heart Reveals Distinct Stress Responses of Right Versus Left Ventricular Fibroblasts.
Circulation: Heart Failure ( IF 9.7 ) Pub Date : 2020-01-09 , DOI: 10.1161/circheartfailure.119.006426
Jeffery C Powers 1 , Abdelkarim Sabri 1 , Dalia Al-Bataineh 1 , Dhruv Chotalia 1 , Xinji Guo 1 , Florence Tsipenyuk 1 , Remus Berretta 1 , Pavithra Kavitha 1 , Heramba Gopi 1 , Steven R Houser 1 , Mohsin Khan 2 , Emily J Tsai 1, 3 , Fabio A Recchia 1, 4
Affiliation  

BACKGROUND The failing right ventricle (RV) does not respond like the left ventricle (LV) to guideline-directed medical therapy of heart failure, perhaps due to interventricular differences in their molecular pathophysiology. METHODS Using the canine tachypacing-induced biventricular heart failure (HF) model, we tested the hypothesis that interventricular differences in microRNAs (miRs) expression distinguish failing RV from failing LV. RESULTS Severe RV dysfunction was indicated by elevated end-diastolic pressure (11.3±2.5 versus 5.7±2.0 mm Hg; P<0.0001) and diminished fractional area change (24.9±7.1 versus 48.0±3.6%; P<0.0001) relative to prepacing baselines. Microarray analysis of ventricular tissue revealed that miR-21 and miR-221, 2 activators of profibrotic and proliferative processes, increased the most, at 4- and 2-fold, respectively, in RV-HF versus RV-Control. Neither miR-21 or miR-221 was statistically significantly different in LV-HF versus LV-Control. These changes were accompanied by more extensive fibrosis in RV-HF than LV-HF. To test whether miR-21 and miR-221 upregulation is specific to RV cellular response to mechanical and hormonal stimuli associated with HF, we subjected fibroblasts and cardiomyocytes isolated from normal canine RV and LV to cyclic overstretch and aldosterone. These 2 stressors markedly upregulated miR-21 and miR-221 in RV fibroblasts but not in LV fibroblasts nor cardiomyocytes of either ventricle. Furthermore, miR-21/221 knockdown significantly attenuated RV but not LV fibroblast proliferation. CONCLUSIONS We identified a novel, biological difference between RV and LV fibroblasts that might underlie distinctions in pathological remodeling of the RV in biventricular HF.

中文翻译:

双心室衰竭心脏中的差异性microRNA-21和microRNA-221上调揭示了右对左心室成纤维细胞的不同应激反应。

背景技术失败的右心室(RV)不能像左心室(LV)那样对心力衰竭的指导性药物治疗做出反应,这可能是由于其分子病理生理学上的心室差异所致。方法使用犬速行引起的双心室心力衰竭(HF)模型,我们检验了microRNA(miRs)表达的心室间差异将RV失败与LV失败区分开的假设。结果舒张末期舒张压升高(11.3±2.5 vs 5.7±2.0 mm Hg; P <0.0001),分数面积变化减小(24.9±7.1 vs 48.0±3.6%; P <0.0001),表明右室功能不全严重。 。心室组织的微阵列分析表明,miR-21和miR-221是2种纤维化和增生过程的激活因子,其增幅最大,分别为4倍和2倍,分别在RV-HF与RV-Control中。LV-HF与LV-Control的miR-21或miR-221均无统计学差异。与LV-HF相比,这些变化伴有RV-HF广泛的纤维化。为了测试miR-21和miR-221的上调是否特异性针对RV细胞对与HF相关的机械和激素刺激的反应,我们对从正常犬RV和LV分离出的成纤维细胞和心肌细胞进行了循环过度拉伸和醛固酮治疗。这2个应激源在RV成纤维细胞中显着上调了miR-21和miR-221,但在任一心室的LV成纤维细胞和心肌细胞中均没有。此外,miR-21 / 221敲低显着减弱了RV,但不减弱LV成纤维细胞的增殖。结论我们确定了一种小说,
更新日期:2020-01-10
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