Li Jian-Chun, Jia Jian, Dong Li, Hu Zhong-Jing, Huang Xiao-Ru, Wang Hong-Lian, Wang Li, Yang Si-Jin, Lan Hui-Yao
Research Center of Integrated Traditional Chinese and Western Medicine, The TCM Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China.
Mol Ther Nucleic Acids. 2023 Jun 26;33:180-190. doi: 10.1016/j.omtn.2023.06.017. eCollection 2023 Sep 12.
Transforming growth factor β (TGF-β)/Smad3 plays a vital role in hypertensive cardiac fibrosis. The long non-coding RNA (lncRNA) Erbb4-IR is a novel Smad3-dependent lncRNA that mediates kidney fibrosis. However, the role of Erbb4-IR in hypertensive heart disease remains unexplored and was investigated in the present study by ultrasound-microbubble-mediated silencing of cardiac in hypertensive mice induced by angiotensin II. We found that chronic angiotensin II infusion induced hypertension and upregulated cardiac , which was associated with cardiac dysfunction, including a decrease in left ventricle ejection fraction (LVEF) and LV fractional shortening (LVFS) and an increase in LV mass. Knockdown of cardiac by short hairpin RNA (shRNA) gene transfer effectively improved the angiotensin II-induced deterioration of cardiac function, although blood pressure was not altered. Furthermore, silencing cardiac also inhibited angiotensin II-induced progressive cardiac fibrosis, as evidenced by reduced collagen I and III, alpha-smooth muscle actin (α-SMA), and fibronectin accumulation. Mechanistically, improved hypertensive cardiac injury by specifically silencing cardiac was associated with increased myocardial and , revealing that may target and to mediate angiotensin II-induced hypertensive cardiac fibrosis. In conclusion, is pathogenic in angiotensin II (Ang II)-induced cardiac remodeling, and targeting may be a novel therapy for hypertensive cardiovascular diseases.
转化生长因子β（TGF-β）/Smad3在高血压性心脏纤维化中起关键作用。长链非编码RNA（lncRNA）Erbb4-IR是一种新型的Smad3依赖性lncRNA，可介导肾纤维化。然而，Erbb4-IR在高血压性心脏病中的作用尚未得到探索，本研究通过超声微泡介导的血管紧张素II诱导的高血压小鼠心脏lncRNA沉默进行了研究。我们发现，慢性输注血管紧张素II可导致高血压并上调心脏lncRNA，这与心脏功能障碍有关，包括左心室射血分数（LVEF）和左心室缩短分数（LVFS）降低以及左心室质量增加。通过短发夹RNA（shRNA）基因转移敲低心脏lncRNA可有效改善血管紧张素II诱导的心脏功能恶化，尽管血压未改变。此外，沉默心脏lncRNA也可抑制血管紧张素II诱导的进行性心脏纤维化，表现为I型和III型胶原蛋白、α-平滑肌肌动蛋白（α-SMA）和纤连蛋白积累减少。机制上，通过特异性沉默心脏lncRNA改善高血压性心脏损伤与心肌miR-145和miR-29增加有关，表明lncRNA可能靶向miR-145和miR-29来介导血管紧张素II诱导的高血压性心脏纤维化。总之，lncRNA在血管紧张素II（Ang II）诱导的心脏重塑中具有致病性，靶向lncRNA可能是高血压性心血管疾病的一种新疗法。
