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. 2019 Oct:118:109296.
doi: 10.1016/j.biopha.2019.109296. Epub 2019 Aug 11.

Direct implantations of erythropoietin and autologous EPCs in critical limb ischemia (CLI) area restored CLI area blood flow and rescued remote AMI-induced LV dysfunction

Fan-Yen Lee  1 , Chi-Wen Luo  2 , Christopher Glenn Wallace  3 , Kuan-Hung Chen  4 , Jiunn-Jye Sheu  5 , Tsung-Cheng Yin  6 , Han-Tan Chai  7 , Hon-Kan Yip  8
Affiliations
Free article

Direct implantations of erythropoietin and autologous EPCs in critical limb ischemia (CLI) area restored CLI area blood flow and rescued remote AMI-induced LV dysfunction

Fan-Yen Lee et al. Biomed Pharmacother. 2019 Oct.
Free article

Abstract

Background: This study tested the hypothesis that intramuscular injections of erythropoietin (EPO) and endothelial progenitor cells (EPC) to critical limb ischemia (CLI; primary treatment site) could also improve heart function in rat after acute myocardial infarction (AMI; remote ischemic organ).

Method: Adult-male SD rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (CLI-AMI), group 3 [CLI-AMI + EPO (10 mg/kg)], group 4 [CLI-AMI + EPCs (1.2 × 106)] and group 5 (CLI-AMI + EPCs + EPO).

Results: By day 21 (end of study period), 2-D echo and Laser doppler showed that left-ventricular injection fraction (LVEF) and the ratio of ischemic to normal blood flow were highest in group 1, lowest in group 2, significantly higher in group 5 than in groups 3 and 4, but not different in the latter two groups (all p < 0.0001). Flow cytometry and ELISA demonstrated that circulating angiogenesis factors were significantly progressively increased from groups 1 to 5 (all p < 0.001). The number of small vessels and protein (CD31/eNOS)/cellular (vWF) expressions reflecting integrity of endothelium exhibited an identical pattern to LVEF whereas protein (VEGF/SDF-1α)/cellular (VEGF) expressions were significantly progressively increased from groups 1 to 5 in quadriceps and heart tissues (all p < 0.0001). Protein expressions of apoptotic (Bax/caspase-3/PARP)/inflammatory (MMP-9) and microscopic findings of ischemic/fibrotic/collagen-deposition areas and DNA-damage marker (γ-H2AX+) were lowest in group 1 and significantly progressively decreased from groups 2 to 5 in quadriceps and heart tissues (all p < 0.0001).

Conclusions: Direct injection of EPO-EPC into CLI effectively restored blood flow in the CLI area and also preserved remote heart function.

Keywords: Angiogenesis; Endothelial progenitor cell; Erythropoietin; Primary and remote organ damage.

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