Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Cardiology, Chi-Mei Medical Center, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
J Mol Cell Cardiol. 2021 May;154:106-114. doi: 10.1016/j.yjmcc.2021.01.003. Epub 2021 Feb 4.
Right ventricular (RV) function is a critical determinant of survival in patients with pulmonary arterial hypertension (PAH). While miR-21 is known to associate with vascular remodeling in small animal models of PAH, its role in RV remodeling in large animal models has not been characterized. Herein, we investigated the role of miR-21 in RV dysfunction using a sheep model of PAH secondary to pulmonary arterial constriction (PAC). RV structural and functional remodeling were examined using ultrasound imaging. Our results showed that post PAC, RV strain significantly decreased at the basal region compared with t the control. Moreover, such dysfunction was accompanied by increases in miR-21 levels. To determine the role of miR-21 in RV remodeling secondary to PAC, we investigated the molecular alteration secondary to phenylephrine induced hypertrophy and miR21 overexpression in vitro using neonatal rat ventricular myocytes (NRVMs). We found that overexpression of miR-21 in the setting of hypertrophic stimulation augmented only the expression of proteins critical for mitosis but not cytokinesis. Strikingly, this molecular alteration was associated with an eccentric cellular hypertrophic phenotype similar to what we observed in vivo PAC animal model in sheep. Importantly, this hypertrophic change was diminished upon suppressing miR-21 in NRVMs. Collectively, our in vitro and in vivo data demonstrate that miR-21 is a critical contributor in the development of RV dysfunction and could represent a novel therapeutic target for PAH associated RV dysfunction.
右心室（RV）功能是肺动脉高压（PAH）患者生存的关键决定因素。虽然 miR-21 已知与 PAH 的小动物模型中的血管重塑有关，但它在大型动物模型中的 RV 重塑中的作用尚未得到描述。在此，我们使用肺动脉收缩（PAC）继发的 PAH 绵羊模型研究了 miR-21 在 RV 功能障碍中的作用。使用超声成像检查 RV 的结构和功能重塑。我们的结果表明，与对照组相比，PAC 后 RV 应变在基底区域明显下降。此外，这种功能障碍伴随着 miR-21 水平的升高。为了确定 miR-21 在 PAC 继发 RV 重塑中的作用，我们研究了苯肾上腺素诱导的肥厚和 miR21 过表达在体外对新生儿大鼠心室肌细胞（NRVMs）的分子改变。我们发现，在肥厚刺激的情况下过表达 miR-21 仅增强了对有丝分裂但不是细胞分裂至关重要的蛋白质的表达。引人注目的是，这种分子改变与我们在绵羊体内 PAC 动物模型中观察到的偏心细胞肥厚表型有关。重要的是，这种肥厚变化在 NRVMs 中抑制 miR-21 后减少。总之，我们的体内外数据表明，miR-21 是 RV 功能障碍发展的关键贡献者，可能代表与 PAH 相关的 RV 功能障碍的新型治疗靶点。
