Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138, Milan, Italy.
Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca, Milan, Italy.
Cardiovasc Diabetol. 2022 Apr 9;21(1):51. doi: 10.1186/s12933-022-01486-9.
Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34 hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34 HSPC function.
In cord blood (CB)-derived CD34 HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and Western Blot respectively. CD34 HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34 HSPC were evaluated.
CD34 HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation, CXCR4/SDF-1α axis activity and metabolic imbalance from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9-39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects.
We provided the first evidence that CD34 HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.
胰高血糖素样肽-1 受体激动剂（GLP-1RAs）已被证明可降低 2 型糖尿病（T2DM）患者的死亡率和心血管事件发生率。由于 T2D 患者循环 CD34 造血干细胞祖细胞（HSPCs）数量和功能受损会增加心血管（CV）风险，我们假设 GLP-1 RAs 发挥 CV 保护作用的机制之一可能与改善 CD34 HSPC 功能的能力有关。
在脐血（CB）衍生的 CD34 HSPC 中，通过 RT-qPCR 和 Western Blot 分别评估 GLP-1 受体（GLP-1R）mRNA、受体蛋白和细胞内信号的表达。将 CD34 HSPC 暴露于高葡萄糖（HG）条件下，并在功能受损之前和之后添加 GLP-1RA 利拉鲁肽（LIRA）。评估 CD34 HSPC 的增殖、CXCR4/SDF-1α 轴活性和细胞内 ROS 产生。
CD34 HSPC 在转录和蛋白水平上表达 GLP-1R。LIRA 治疗可预防和挽救 HSPC 增殖、CXCR4/SDF-1α 轴活性和 HG 诱导的代谢失衡。LIRA 刺激可促进细胞内 cAMP 积累以及 ERK1/2 和 AKT 信号转导的激活。选择性 GLP-1R 拮抗剂 exendin（9-39）可阻断 LIRA 依赖性 ERK1/2 和 AKT 磷酸化以及相关的保护作用。
我们首次提供了证据表明 CD34 HSPC 表达 GLP-1R，并且 LIRA 可以对由于 HG 暴露而导致的细胞功能障碍产生有利影响。这些发现为 GLP-1 RAs 在 T2DM 患者中的有利 CV 作用开辟了新的视角。
