Molecular Cardiology Program, Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, Birmingham, AL 35294, USA.
Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Theranostics. 2021 Jul 6;11(16):7995-8007. doi: 10.7150/thno.50990. eCollection 2021.
The conserved long non-coding RNA (lncRNA) myocardial infarction associate transcript () was identified for its multiple single-nucleotide polymorphisms that are strongly associated with susceptibility to MI, but its role in cardiovascular biology remains elusive. Here we investigated whether regulates cardiac response to pathological hypertrophic stimuli. Both an angiotensin II (Ang II) infusion model and a transverse aortic constriction (TAC) model were used in adult WT and -null knockout (-KO) mice to induce pathological cardiac hypertrophy. Heart structure and function were evaluated by echocardiography and histological assessments. Gene expression in the heart was evaluated by RNA sequencing (RNA-seq), quantitative real-time RT-PCR (qRT-PCR), and Western blotting. Primary WT and -KO mouse cardiomyocytes were isolated and used in Ca transient and contractility measurements. Continuous Ang II infusion for 4 weeks induced concentric hypertrophy in WT mice, but to a lesser extent in -KO mice. Surgical TAC for 6 weeks resulted in decreased systolic function and heart failure in WT mice but not in -KO mice. In both models, -KO mice displayed reduced heart-weight to tibia-length ratio, cardiomyocyte cross-sectional area, cardiomyocyte apoptosis, and cardiac interstitial fibrosis and a better-preserved capillary density, as compared to WT mice. In addition, Ang II treatment led to significantly reduced mRNA and protein expression of the Ca cycling genes Sarcoplasmic/endoplasmic reticulum Ca ATPase 2a (SERCA2a) and ryanodine receptor 2 (RyR2) and a dramatic increase in global RNA splicing events in the left ventricle (LV) of WT mice, and these changes were largely blunted in -KO mice. Consistently, cardiomyocytes isolated from -KO mice demonstrated more efficient Ca cycling and greater contractility. Ablation of attenuates pathological hypertrophy and heart failure, in part, by enhancing cardiomyocyte contractility.
保守的长非编码 RNA（lncRNA）心肌梗死相关转录物（）因其多个与 MI 易感性密切相关的单核苷酸多态性而被鉴定出来，但它在心血管生物学中的作用仍不清楚。在这里，我们研究了是否调节心脏对病理性肥大刺激的反应。我们使用血管紧张素 II（Ang II）输注模型和横主动脉缩窄（TAC）模型，在成年 WT 和 -null 敲除（-KO）小鼠中诱导病理性心肌肥大。通过超声心动图和组织学评估评估心脏结构和功能。通过 RNA 测序（RNA-seq）、定量实时 RT-PCR（qRT-PCR）和 Western 印迹评估心脏中的基因表达。分离 WT 和 -KO 小鼠原代心肌细胞，并用于 Ca 瞬变和收缩性测量。连续 Ang II 输注 4 周诱导 WT 小鼠发生向心性肥大，但在 -KO 小鼠中程度较轻。6 周的外科 TAC 导致 WT 小鼠收缩功能下降和心力衰竭，但在 -KO 小鼠中则没有。在两种模型中，与 WT 小鼠相比，-KO 小鼠的心脏重量与胫骨长度比、心肌细胞横截面积、心肌细胞凋亡、心脏间质纤维化减少，毛细血管密度增加。此外，Ang II 处理导致 WT 小鼠左心室（LV）中 Ca 循环基因肌浆/内质网 Ca ATP 酶 2a（SERCA2a）和兰尼碱受体 2（RyR2）的 mRNA 和蛋白表达显著降低，并且整体 RNA 剪接事件明显增加，而这些变化在 -KO 小鼠中则大大减弱。一致地，来自 -KO 小鼠的心肌细胞表现出更有效的 Ca 循环和更大的收缩性。 缺失在一定程度上通过增强心肌细胞的收缩性来减轻病理性肥大和心力衰竭。
