长链非编码RNA uc.323通过抑制LSD1/MMP-2途径改善心肌纤维化的研究

心力衰竭(HF)是各种心血管疾病进展到终末阶段的共同表现，而心肌纤维化是HF发生的重要病理生理机制。目前临床上仍缺乏有效且特异的心肌纤维化治疗药物。课题组先前报道了长链非编码RNA uc.323可以抑制心肌肥厚，但在心肌纤维化中的作用尚不清楚。我们前期预实验显示：uc.323基因缺失在压力过负荷诱导的HF模型中显著加重心肌纤维化水平，且沉默uc.323促进心肌成纤维细胞的增殖和胶原合成，同时体内外实验均发现uc.323表达缺失或下降可促进LSD1和MMP-2的转录表达。由此推测uc.323可能通过调控LSD1/MMP-2途径抑制心肌纤维化。因此，本研究拟利用uc.323敲除和条件性过表达小鼠构建心肌纤维化模型，从体内外水平探讨uc.323对心肌纤维化的调控作用，并深入阐明抑制LSD1/MMP-2途径是否为其调控心肌纤维化的核心分子机制，为寻找新型的心肌纤维化治疗靶点提供重要的科学理论依据。

Heart failure (HF) is a common manifestation at the end stage of various forms of cardiovascular diseases, and cardiac fibrosis is an important pathophysiological mechanism of HF. However, there is still a lack of effective and specific therapeutic drugs that target cardiac fibrosis in clinical practice. Our previously published data demonstrated that uc.323 was a conserved long non-coding RNA that could inhibit cardiac hypertrophy. However, the role of uc.323 in cardiac fibrosis is still unclear. Our preliminary experiments showed that deletion of uc.323 significantly increased the level of cardiac fibrosis in a pressure-overload HF model of mice, and silencing or down-regulation of uc.323 promoted the proliferation and collagen synthesis of cardiac fibroblasts. Moreover, in vivo and in vitro experiments confirmed that silencing or down-regulation of uc.323 could promote the transcription expression of LSD1 and MMP-2. Accordingly, we hypothesize that uc.323 may attenuate cardiac fibrosis via inhibiting the LSD1/MMP-2 pathway. In this study, we aimed to investigate the role of uc.323 in cardiac fibrosis from the levels of in vivo and in vitro models of cardiac fibrosis using uc.323 knockout mice and transgenic mice overexpressing uc.323 in cardiac fibroblasts, and further clarify whether inhibition of the LSD1/MMP-2 pathway is the potential molecular mechanism, which may provide the scientific theoretical basis for new anti-fibrosis therapeutic targets.