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Clinical and research medicine: Acute coronary syndrome
e0429 Patients with type 2 diabetes exhibit impaired mobilisation of endothelial progenitor cells after acute myocardial infarction mediated by VEGF/Akt/eNOS/MMP9 pathway
  1. Shen Yu,
  2. Lu Wen,
  3. Gu Rong,
  4. Wan Kun,
  5. Kang Lina
  1. 1Department of Cardiology, Nanjing Gulou Hosital

Abstract

Background Type 2 diabetes mellitus (T2DM) is a main risk of coronary artery disease (CAD), with impairment of endothelial progenitor cells (EPCs) function thought to be a contributing factor. EPCs from bone marrow are mobilised in response to ischaemia, and play an important role in neovasculation.

Objective The aim of this study is to investigate EPC mobilisation after acute myocardial infarction (AMI) in T2DM patients is responsible for the impairment of neovasculation. We hypothesised that it is mediated by the downregulation of vascular endothelial growth factor (VEGF) pathway in bone marrow.

Research design and methods We recruited 22 patients who were admitted to hospital following AMI. 11 had T2DM and 11 were non-diabetic. Circulating CD45-/low/CD34+/CD133+/KDR+ EPCs were quantified by flow cytometry, at different time points up to Day 28 post-AMI, as well as plasma vascular endothelial growth factor (VEGF), stromal cell-derived factor (SDF) -1α and high sensitivity C-reactive protein (hsCRP). Rats with fat-diet, streptozotocin-induced T2DM were used to test the EPC-mobilising pathway in bone marrow. Circulating EPCs were identified as c-kit+/CD34+ cells after a myocardial infarction operation. VEGF, phosphorylation of Akt, endothelial nitric oxide synthase (eNOS), and activity of matrix metalloproteinase (MMP)-9 in bone marrow were measured.

Results Following AMI, patients with T2DM exhibited a delay (peak time: Day 7 vs Day 5) and a decrease in magnitude (peak level: 140±48/106 mononuclear cells (MNCs) vs 246±100/106 MNCs, p<0.05) of EPC mobilisation, as compared to non-diabetic patients. This is similar to what we found in the T2DM rat model following AMI surgery. The first peak of EPC mobilisation in diabetic rats occurred 2 days later (Day 3 vs Day 1), and lower than nondiabetic rats (101±44/105MNCs vs 260±64/105MNCs respectively, p<0.05). In the human study, the impairment in EPC mobilisation was accompanied by augmented upregulation of plasma VEGF, stromal cell-derived factor-1α and high sensitivity C-reactive protein following AMI, in T2DM vs non-diabetic patients. After myocardial infarction, downregulation of VEGF, Akt, eNOS and MMP9 in bone marrow were detected in T2DM rats comparing to non-diabetic group.

Conclusions This is the first demonstration that bone marrow-derived EPC mobilisation following AMI is impaired in patients with T2DM. Such impairment is likely to have important contribution to the poor collateralization observed in such patients in response to vascular occlusive disease.

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