机械应力下环状RNA circ-XPR1靶向miR-98-5p参与心肌微血管新生的调控及机制

Impairment of myocardial angiogenesis is an important factor in cardiac dysfunction caused by mechanical stress. It is of importance to study the regulatory mechanism of myocardial angiogenesis under mechanical stress to prevent heart failure induced by hypertension. We found that impairment of myocardial angiogenesis was accompanied by elevation of miR-98-5p in the heart. The exosomes secreted by cardiomyocytes following mechanical stretch inhibited angiogenesis. The expression of miR-98-5p increased significantly in the exosomes shown by RNA sequencing. Furthermore, by bioinformatics analysis, we observed that miR-98-5p can target multiple 3’UTR of many pro-angiogenic factors and circ-CRP1 with highly expression in the heart can target miR-98-5p with sponge effect. Therefore, it hints that miR-98-5p inhibit myocardial angiogenesis and circ-CRP1 target miR-98-5p through ceRNA, promoting myocardial angiogenesis and maintaining cardiac adaptation to mechanical stress. The aim of this study is to explore the regulatory role of circ-CRP1 in promoting myocardial angiogenesis from aspects of organ, cell and molecular level, and to elucidate the regulatory pathways of exosomes and miR-98-5p involved. This study will provide new targets for early intervention and prevention of heart failure.

心肌微血管新生障碍是心肌功能失代偿的重要因素, 研究机械应力下心肌微血管新生机制对防治高血压导致的心衰十分重要。我们发现，心肌微血管新生功能损伤会伴随着miR-98-5p表达的升高；机械应力刺激下的心肌细胞外泌体能抑制微血管新生，测序结果显示外泌体中miR-98-5p表达升高显著；生物信息学分析，miR-98-5p靶向调节多个促血管生成效应分子，而心脏高表达的circ-CRP1能特异性靶向结合miR-98-5p。因此提示，miR-98-5p可以抑制心肌微血管新生；进而在机械应力下， circ-CRP1通过ceRNA模式作用于miR-98-5p，促进心肌微血管新生，维持心脏的代偿。本研究拟从器官、细胞及分子水平上，探讨circ-CRP1促心肌微血管新生的调节作用，阐明心肌细胞外泌体和miR-98-5p参与下的调控通路， 为心衰早期干预和防治提供新靶点。

心肌微血管新生障碍是心肌功能失代偿的重要因素, 研究机械应力下心肌微血管新生机制对防治高血压导致的心衰十分重要。该研究发现，心肌微血管新生功能损伤会伴随着miR-98-5p表达的升高；在机械应力下，miR-98-5p能够促进心肌微血管新生，circ-RAB3IP1也能够促进心肌微血管新生 ，但是circ-RAB3IP1并不能够通过ceRNA 方式调控 miR-98-5p的表达；机械应力下，心肌细胞 miR-98-5p 和circ-RAB3IP1都可以通过外泌体途径和非外泌体途径旁分泌促进血管新生；心肌细胞源性的circ-RAB3IP1通过调节IGF1、IGF1R、MEF2 或 STAT3，调节血管新生相关细胞因子的生成，进而参与心肌微血管新生的调节。该研究阐明了 circ-RAB3IP1和 miR-98-5p 在机械应力导致的心肌肥厚中协同参与微血管新生的调控网络，并揭示了外泌体介导的细胞间相互作用，完善心肌微血管新生调节的机制，为临床心力衰竭的治疗提供了新的思路和作用靶点。