心脏纤维化是导致心力衰竭的关键病理过程，骨髓源性纤维细胞前体的摄取与分化在其中起重要作用，但机制尚不清楚。循环单核细胞和心室成纤维细胞表达KCa3.1，且受Ang II刺激上调。预实验发现阻断KCa3.1明显减轻压力超负荷引起的心脏纤维化。假设：KCa3.1介导骨髓源性循环单核细胞向心脏募集和心脏炎症微环境，促进浸润的单核细胞分化为肌成纤维细胞，导致心脏纤维化。本项目分别通过Ang II灌输和腹主动脉缩窄建立大鼠压力超负荷致心脏纤维化模型，分别应用KCa3.1特异性阻断剂和腺病毒载体介导的短发夹RNA探索阻断KCa3.1对心脏纤维化的影响；通过分离成年健康志愿者循环单核细胞、CD4+ T细胞和培养人脐静脉内皮细胞，研究KCa3.1在循环单核细胞跨内皮迁移并向肌成纤维细胞分化中的作用。研究结果不仅可以阐明KCa3.1在心脏纤维化发生发展中的作用与机制，也将为研发防治心脏纤维化的药物提供线索。

Cardiac fibrosis is a core pathologic process associated with heart failure. The uptake and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. However, the specific cellular and molecular mechanisms of governing this process are still not well defined. The intermediate-conductance Ca2+-activated K+ (KCa3.1) channels express in both of ventricular fibroblasts and circulating mononuclear cells in rats, and is upregulated by angiotensin II (Ang II). Primal study from our group indicated that inhibition of KCa3.1 channels alleviated cardiac fibrosis induced by pressure-overload. We hypothesize that KCa3.1 mediates the recruitment of bone marrow-derived circulating mononuclear cells into heart and inflammatory microenvironment in heart, promotes the infiltrated mononuclear cells to differentiate into myofibroblasts, and results in cardiac fibrosis. The present project is designed to establish pressure-overload induced cardiac fibrosis models in rats by Ang II infusion and abdominal aortic constriction, and explore the effect of inhibiting KCa3.1 on cardiac fibrosis through treatment with specific KCa3.1 blocker and adenovirus-mediated short hairpin RNA (shRNA), respectively. By separating circulating mononuclear cells and CD+ T cells from adult healthy volunteer and culturing human umbilical vein endothelial cells, we will study the role of KCa3.1 in transendothelial migration of circulating mononuclear cells and their differentiation into myofibroblast. The results will elucidate the role and mechanism of KCa3.1 in the development and progression of cardiac fibrosis, and also provide valuable insights for therapeutic approaches to prevent cardiac fibrosis.