From the Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix (A.M.G., T.M.H.).
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ (M.D.D.B., J.S.T., M.J.H.).
Hypertension. 2021 Mar 3;77(3):904-918. doi: 10.1161/HYPERTENSIONAHA.120.16352. Epub 2021 Jan 25.
Transient ACE (angiotensin-converting enzyme) inhibition in spontaneously hypertensive rats is known to protect against future injury-induced cardiac inflammation, fibrosis, and dysfunction; however, the mechanisms of protection have not been delineated. Here, we used single-cell RNA sequencing to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in cardiac fibroblast subpopulations. Adult male spontaneously hypertensive rats (11 weeks old, hypertensive with cardiac hypertrophy) were treated for 2 weeks with an ACE inhibitor, enalapril (30 mg/kg per day, PO), or water (untreated spontaneously hypertensive rats) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to single-cell RNA sequencing. Nine clusters of fibroblasts were identified, with 98% of cells in clusters 0 to 6. The transient treatment produced significant changes both within and across clusters. Cluster 1 depicted a highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (eg, , and ; all <1×10). Clusters 2 to 5 reflected proliferative, moderately fibrogenic, translationally active, and less inflammatory subsets of fibroblasts, all of which exhibited attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.
自发性高血压大鼠（SHR）短暂的 ACE（血管紧张素转换酶）抑制已知可预防未来损伤引起的心脏炎症、纤维化和功能障碍；然而，保护机制尚未阐明。在这里，我们使用单细胞 RNA 测序来检验假设，即短暂的 ACE 抑制剂治疗会诱导心脏成纤维细胞亚群的持续转变。成年雄性 SHR（11 周龄，高血压伴心肌肥厚）接受 ACE 抑制剂依那普利（30mg/kg/天，PO）或水（未治疗的 SHR）治疗 2 周，随后进行 2 周洗脱期（每组 n=7）。从左心室分离心脏成纤维细胞，并进行单细胞 RNA 测序。鉴定出 9 个成纤维细胞簇，其中 0 到 6 簇中的 98%的细胞。短暂的治疗在簇内和簇间都产生了显著的变化。簇 1 描绘了一个高度纤维化的基因谱，簇 6 是进入簇 1 的通道。短暂的 ACE 抑制耗尽了通道并扩展了簇 0，簇 0 是纤维化程度最低的。此外，在簇 1 成纤维细胞中，ACE 抑制降低了单个纤维化基因的表达（例如、和；所有 <1×10）。簇 2 到 5 反映了增殖、中度纤维化、翻译活跃和炎症程度较低的成纤维细胞亚群，所有这些亚群在短暂的 ACE 抑制后纤维化基因表达均减弱。总之，短暂的 ACE 抑制改变了心脏成纤维细胞亚群和激活程度，导致整体纤维化表型降低。
