Bakhashab Sherin, Ahmed Fahad W, Schulten Hans-Juergen, Bashir Ayat, Karim Sajjad, Al-Malki Abdulrahman L, Gari Mamdooh A, Abuzenadah Adel M, Chaudhary Adeel G, Alqahtani Mohammed H, Lary Sahira, Ahmed Farid, Weaver Jolanta U
Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia.
Cardiovasc Diabetol. 2016 Feb 9;15:27. doi: 10.1186/s12933-016-0344-2.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with diabetes mellitus (DM). To identify the most effective treatment for CVD, it is paramount to understand the mechanism behind cardioprotective therapies. Although metformin has been shown to reduce CVD in Type-2 DM clinical trials, the underlying mechanism remains unexplored. CD34(+) cell-based therapies offer a new treatment approach to CVD. The aim of this study was to investigate the effect of metformin on the angiogenic properties of CD34(+) cells under conditions mimicking acute myocardial infarction in diabetes.
CD34(+) cells were cultured in 5.5 or 16.5 mmol/L glucose ± 0.01 mmol/L metformin and then additionally ± 4 % hypoxia. The paracrine function of CD34(+) cell-derived conditioned medium was assessed by measuring pro-inflammatory cytokines, vascular endothelial growth factor A (VEGFA), and using an in vitro tube formation assay for angiogenesis. Also, mRNA of CD34(+) cells was assayed by microarray and genes of interest were validated by qRT-PCR.
Metformin increased in vitro angiogenesis under hyperglycemia-hypoxia and augmented the expression of VEGFA. It also reduced the angiogenic-inhibitors, chemokine (C-X-C motif) ligand 10 (CXCL10) and tissue inhibitor of metalloproteinase 1 (TIMP1) mRNAs, which were upregulated under hyperglycemia-hypoxia. In addition metformin, increased expression of STEAP family member 4 (STEAP4) under euglycemia, indicating an anti-inflammatory effect.
Metformin has a dual effect by simultaneously increasing VEGFA and reducing CXCL10 and TIMP1 in CD34(+) cells in a model of the diabetic state combined with hypoxia. Therefore, these angiogenic inhibitors are promising therapeutic targets for CVD in diabetic patients. Moreover, our data are commensurate with a vascular protective effect of metformin and add to the understanding of underlying mechanisms.
心血管疾病（CVD）是糖尿病（DM）患者发病和死亡的主要原因。为了确定治疗CVD的最有效方法，了解心脏保护疗法背后的机制至关重要。尽管在2型糖尿病临床试验中已证明二甲双胍可降低CVD，但其潜在机制仍未得到探索。基于CD34(+)细胞的疗法为CVD提供了一种新的治疗方法。本研究的目的是在模拟糖尿病急性心肌梗死的条件下，研究二甲双胍对CD34(+)细胞血管生成特性的影响。
将CD34(+)细胞在5.5或16.5 mmol/L葡萄糖±0.01 mmol/L二甲双胍中培养，然后再分别置于±4%低氧环境中。通过测量促炎细胞因子、血管内皮生长因子A（VEGFA），并使用体外血管生成管形成试验来评估CD34(+)细胞来源的条件培养基的旁分泌功能。此外，通过微阵列分析CD34(+)细胞的mRNA，并通过qRT-PCR验证感兴趣的基因。
在高血糖-低氧条件下，二甲双胍增加了体外血管生成并增强了VEGFA的表达。它还降低了血管生成抑制剂、趋化因子（C-X-C基序）配体10（CXCL10）和金属蛋白酶组织抑制剂1（TIMP1）的mRNA，这些在高血糖-低氧条件下上调。此外，二甲双胍在正常血糖条件下增加了STEAP家族成员4（STEAP4）的表达，表明具有抗炎作用。
在糖尿病状态合并低氧的模型中，二甲双胍通过同时增加CD34(+)细胞中的VEGFA并降低CXCL10和TIMP1而具有双重作用。因此，这些血管生成抑制剂是糖尿病患者CVD的有前景的治疗靶点。此外，我们的数据与二甲双胍的血管保护作用一致，并增加了对潜在机制的理解。
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