Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND 58108, U.S.A.
Museum District Eye Clinic, Houston, TX, U.S.A.
Clin Sci (Lond). 2021 Jan 29;135(2):367-385. doi: 10.1042/CS20201133.
Diabetes increases the risk for ischemic vascular diseases, which is further elevated in older adults. Bone marrow-derived hematopoietic CD34+ stem/progenitor cells have the potential of revascularization; however, diabetes attenuates vasoreparative functions. Angiotensin-converting enzyme 2 (ACE2) is the vasoprotective enzyme of renin-angiotensin system in contrast with the canonical angiotensin-converting enzyme (ACE). The present study tested the hypothesis that diabetic dysfunction is associated with ACE2/ACE imbalance in hematopoietic stem/progenitor cells (HSPCs) and that increasing ACE2 expression would restore reparative functions. Blood samples from male and female diabetic (n=71) or nondiabetic (n=62) individuals were obtained and CD34+ cells were enumerated by flow cytometry. ACE and ACE2 enzyme activities were determined in cell lysates. Lentiviral (LV) approach was used to increase the expression of soluble ACE2 protein. Cells from diabetic older adults (DB) or nondiabetic individuals (Control) were evaluated for their ability to stimulate revascularization in a mouse model of hindlimb ischemia (HLI). DB cells attenuated the recovery of blood flow to ischemic areas in nondiabetic mice compared with that observed with Control cells. Administration of DB cells modified with LV-ACE2 resulted in complete restoration of blood flow. HLI in diabetic mice resulted in poor recovery with amputations, which was not reversed by either Control or DB cells. LV-ACE2 modification of Control or DB cells resulted in blood flow recovery in diabetic mice. In vitro treatment with Ang-(1-7) modified paracrine profile in diabetic CD34+ cells. The present study suggests that vasoreparative dysfunction in CD34+ cells from diabetic older adults is associated with ACE2/ACE imbalance and that increased ACE2 expression enhances the revascularization potential.
糖尿病增加缺血性血管疾病的风险，老年患者的风险进一步增加。骨髓来源的造血 CD34+ 干细胞具有血管再生的潜力；然而，糖尿病会减弱血管修复功能。血管紧张素转换酶 2 (ACE2) 是肾素-血管紧张素系统的血管保护酶，与经典的血管紧张素转换酶 (ACE) 相反。本研究检验了以下假设：糖尿病功能障碍与造血干细胞/祖细胞 (HSPC) 中的 ACE2/ACE 失衡有关，增加 ACE2 表达将恢复修复功能。从男性和女性糖尿病（n=71）或非糖尿病（n=62）个体中获得血液样本，并通过流式细胞术计数 CD34+细胞。在细胞裂解物中测定 ACE 和 ACE2 酶活性。采用慢病毒 (LV) 方法增加可溶性 ACE2 蛋白的表达。评估来自糖尿病老年患者 (DB) 或非糖尿病个体 (Control) 的细胞在小鼠后肢缺血 (HLI) 模型中刺激血管再生的能力。与 Control 细胞相比，DB 细胞削弱了非糖尿病小鼠缺血区域血流的恢复。用 LV-ACE2 处理的 DB 细胞导致血流完全恢复。糖尿病小鼠的 HLI 导致截肢，这与 Control 或 DB 细胞都无法逆转。LV-ACE2 修饰的 Control 或 DB 细胞可恢复糖尿病小鼠的血流。Ang-(1-7) 处理体外改变了糖尿病 CD34+细胞的旁分泌谱。本研究表明，糖尿病老年患者 CD34+细胞的血管修复功能障碍与 ACE2/ACE 失衡有关，增加 ACE2 表达可增强血管再生潜力。
