Influence of Hypoxia Inducible Factor-1α of Endothelial Progenitor Cells on Left Ventricular Function in Experimental Myocardial Infarction

2022 ◽  
Vol 12 (4) ◽  
pp. 731-738
Author(s):  
Zhitang Chang ◽  
Guotai Sheng ◽  
Yizhong Zhou ◽  
Zhiyong Wu ◽  
Guobo Xie ◽  
...  

Based on the promotion of myocardial activity via endothelial progenitor cells (EPCs) subsequent to acute myocardial infarction (AMI), our research was designed to explore the influence of excessive HIF-1α expression in expanded EPCs (eEPCs) on promotion of the activity of left ventricle subsequent to MI. Isolation of EPCs from cord blood was performed before transduction with the help of retroviral vector with or without HIF-1α expression. Transplantation was performed subsequent to ligation of the left anterior descending coronary artery in mice. Ejection fraction (EF) of left ventricle was promoted via transplantation after 2 weeks. Excessive HIF-1α expression enhanced EF of left ventricle and decreased the extent of MI. It was revealed via functional studies that excessive HIF-1α expression enhanced proliferation of EPCs triggered by low oxygen concentration and suppressed cell death in the region of infarction. Moreover, markers of endothelium CD31, VEGF, and eNOS were upregulated. Transplantation of eEPCs with excessive HIF-1α expression in AMI can promote myocardial activities by increasing differentiation, generation of vessels, proliferation of eEPCs, and suppressing cell death. The above findings propose that regulation of EPCs via HIF-1α enhances the activity as well as mobilization of EPCs, indicating that reinforcement of expression of HIF-1α is beneficial for coronary heart disease.

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Martina Knoedler ◽  
Eliane Weidl ◽  
Sandra Gawehn ◽  
Maren Schurmann ◽  
Andreas Stein ◽  
...  

Background: Recent studies suggest that endothelial progenitor cells (EPC) from bone marrow or peripheral blood improve myocardial function in experimental myocardial infarction (MI). Since applications for cell therapy are limited by the number of available cells, expansion of EPC may facilitate its therapeutic use in ischemic disease. The aim of this study was to expand late outgrowth EPC from peripheral blood from patients with acute myocardial infarction, characterize them and investigate their therapeutic effect in experimental MI. Methods and Results: Venous blood samples were obtained from patients with acute MI (n=51), stable angina (sAP, n=57) and healthy controls (H,n=47). CD34+ cells were isolated using immunomagnetic beads (Miltenyi Biotec). CD34+ cells cultured on fibronectin in endothelial cell medium formed colonies after 1–2 weeks and were further expanded for up to 3 months to generate late outgrowth EPC (eEPC). Expansion was observed up to 2.9x10′9 (MI), 11x10′9 (sAP) and 7x10′9 cells (H) with a mean culture duration of 61 days. Expanded cells showed an endothelial morphology and expressed endothelial surface markers (CD31, VEGF-R2, CD105). Intramyocardial transplantion of 1x10′6 eEPC in experimental myocardial infarction in athymic nude rats revealed improvement in echocardiographic ejection fraction after 2 weeks. This was associated with enhanced vessel density after 1 week and increased mRNA expression of HGF. No differences in infarct size were observed. Similarly in a chronic model of myocardial infarction (eEPC transplantation 1 week after MI) myocardial function significantly improved after 5 weeks in comparison to the control group. Conclusion: Expansion of eEPC from circulating CD34+ cells in patients with coronary artery disease is feasible and improves myocardial function after local transplantation in acute and chronic myocardial infarction. The large number of generated eEPC may prove benefical for therapeutic use and this advantage may prevail time-consuming expansion procedures.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Andreas Stein ◽  
Antti Saraste ◽  
Marcus Makowski ◽  
Sandra Kühnel ◽  
Elisabeth Weidl ◽  
...  

Background : Experimental studies showed that application of expanded endothelial progenitor cells (eEPC) after myocardial infarction improves cardiac function by enhancing vasculogenesis and by paracrine effects. Erythropoietin beta (EPO) could further improve myocardial function through its anti-apoptotic properties. Methods : Acute myocardial ischemia was induced by ligation of the left anterior descending coronary artery of 23 male athymic nude rats and reperfusion was initiated after 30 minutes. Either 1×10^6 eEPC alone (n=8), 50 IU erythropoietin beta alone (n=7) or eEPC and EPO (n=8) were injected intramyocardially into the border zone of the ischemic area. eEPC were attained by expanding CD34+ cells isolated from cord blood in endothelial medium for 6 –10 passages. A control group did not receive cells or erythropoietin (n=5). After 4 weeks global and regional left ventricular function was measured by MRI in 2- and 4-chamber long-axis series (Philips Achieva MR Scanner). Immunhistology was used to determine vessel densitiy (SMC actin) and infiltrating monocytes (CD68) after 3 days (n=15) and 4 weeks. Results : Global left ventricular function after 4 weeks was higher in rats that received eEPC alone (58±3%, p=.02) or eEPC + EPO (58±6%, p=.01) compared to the control group (54±5%). No changes were found for rats treated with EPO alone (52±4%). Analysis of the regional wall movement showed a further improvement of the movement of the antero-lateral segments only in rats that obtained eEPC + EPO. The number of CD68+ mononuclear cells after 3 days was highest in rats that were treated with eEPC + EPO. This was associated with an increase in vessel density after 4 weeks. In vitro experiments revealed a dose-dependent inhibition of apoptosis by EPO in eEPC. Conclusion: Intramyocardial transplantation of eEPCs + EPO further improved anterolateral wall motion as compared to EPC alone. Improved eEPC survival, alterations in local inflammatory responses and neovascularization may contribute to this effect.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Motoo Date ◽  
Hiroshi Ito ◽  
Katsuomi Iwakura ◽  
Atsunori Okamura ◽  
Yasushi Koyama ◽  
...  

Endothelial progenitor cells (EPC) increase after acute myocardial infarction and may contribute to neovascularization in the infarct zone. The aim of this study was to elucidate the relation of EPC release to recovery of microvascualr and myocardial function. Eighteen patients with acute myocardial infarction (AMI) undergoing primary PCI within 12 hours after onset were enrolled. CD34 + cells were counted at days-1, 7 and 14 as an index of EPC. We performed triggered end-systolic myocardial contrast echocardiography (MCE) at every 6 cardiac cycles with continuous infusion of Levovist at days-2 and 14. We performed left ventriculography 6 months later to calculate left ventricular ejection fraction (LVEF) and end-diastolic volume index (LVEDVI). The number of EPC at day-7 was significantly higher than that at day-1 (1.29+/−0.75 vs. 2.10+/−1.25/micL, p<0.001). It was correlated with myocardial blood volume (MBV), that implies microvascular integrity, at day-14 measured from MCE image (r 2 =0.652, p<0.005) and with an increase in MBV from day-1 to day-7 (r 2 =0.533, p<0.005). To evaluate the correlation between EPC and LV function, we divided patients into two groups according to the number of EPC at day-7. LVEF and LVEDVI were comparable between the higher number of EPC and the lower number of EPC groups (49.3+/−12.2 vs. 52.4+/−8.1%, 65.2+/−13.1 vs. 69.1+/−16.6ml/m 2 ). EPC spontaneously released after AMI and number of released EPC is correlated to the amount of neovascularization in the infarct zone. The number of EPC was not necessarily related to the functional improvement or attenuation of LV remodeling.


Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Poay Sian S Lee ◽  
Lei Ye ◽  
Yei-Tsung Chen ◽  
Eric Yin Hao Khoo ◽  
Tiong Cheng Yeo ◽  
...  

Introduction: Diabetes and obesity are associated with endothelial dysfunction and may impair circulating endothelial progenitor cells (EPCs). Thymosin beta-4 (Tβ4), a novel peptide with angiogenic properties, may improve EPC number and function. Hypothesis: We aim to transplant allogenic Tβ4-treated EPCs in Zucker Diabetic Fatty (ZDF) rats with myocardial infarction (MI) and hypothesize that Tβ4-treated EPCs may improve cardiac function, vasculogenesis and upregulate angiogenic cytokines and genes, compared to non-treated EPCs and controls. Methods: The left anterior descending coronary artery was permanently ligated to induce experimental MI on ZDF rats (n=19), divided into MI+saline(n=6); MI+EPCs (n=6) and MI+Tβ4-treated EPCs (n=7). Peripheral blood mononuclear cells were harvested from ZDF rats and isolated using Ficoll density gradient centrifugation and grown on fibronectin-coated plates. EPCs were treated with Tβ4 (1μg/mL) on day 7. At day 10, allogenic EPCs were harvested and transplanted into the peri-infarcted myocardium. Echocardiographic examination including strain assessment, immunohistological assessments and assays of angiogenic cytokines were performed 6 weeks after surgery. Results: Left ventricular (LV) ejection fraction was improved in Tβ4-treated EPCs (72.0±7.6%) and non-treated EPCs rats (80.5±5.9%) compared to control MI rats (64.8±19.7%) (P=0.04). Similar improvement was observed in LV radial strain rate in rats with Tβ4-treated EPCs (-7.22±1.24 1/s) and non-treated EPCs (-6.67±2.66 1/s) compared to MI only (-4.08±3.75 1/s) (P<0.01). Vascular density (CD31) and c-kit density (CD117) were significantly upregulated in Tβ4-treated EPCs rats compared to MI (P=0.03; P=0.005 respectively) and non-treated EPCs rats (P=0.04; P=0.04 respectively). Angiogenic cytokines of PDGF-BB, IGF-1 and VEGF levels were increased by 1.5 fold in Tβ4-treated EPCs and supported by similar trend in mRNA levels compared to non-treated EPCs (P<0.01). Conclusions: ZDF rats with Tβ4-treated EPCs had significant improvement in cardiac function, increased vasculogenesis and upregulation of angiogenic cytokines and genes. This suggests that Tβ4 may be beneficial in enhancing efficacy of EPCs in cell-based therapies.


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