Ex vivo Akt/HO-1 gene therapy to human endothelial progenitor cells enhances myocardial infarction recovery.

Abstract

The aim of this study was to evaluate the overexpression of genes central to cell survival and angiogenesis to enhance the function of human late outgrowth endothelial progenitor cells (EPCs) and their utility for infarct recovery. Ischemic myocardial injury creates a hostile microenvironment, which is characterized by hypoxia, oxidative stress, and inflammation. The infarct microenvironment prevents adhesion, survival, and integration of cell transplants that promote neovascularization. EPCs are dysfunctional as a result of risk factors in cardiovascular patients. Protein kinase B (Akt) and heme-oxygenase-1 (HO-1) are intracellular proteins that play an important role in angiogenesis and cell survival. Late outgrowth EPCs transduced ex vivo with Akt and HO-1 demonstrate improved adhesion to extracellular matrix, improved migration toward human cardiomyocytes, and an improved paracrine profile under stress. Enhanced late outgrowth EPCs reduce the tumor necrosis factor-α (TNF-α) burden both in vitro and in vivo, attenuating nuclear factor-κB (NF-κB) activity and promoting cell survival. Akt and HO-1 enhance late outgrowth EPC neovascularization, resulting in improved cardiac performance and reduced negative remodeling after myocardial infarction in nude mice. Alteration of the infarct microenvironment through gene modification of human late outgrowth EPCs enhances the function and integration of transplanted cells for restoration of cardiac function.

• Authors: Keith R Brunt, Jun Wu, Zhilin Chen, Daniel Poeckel, Ryan A Dercho, Luis G Melo, Colin D Funk, Christopher A Ward, Ren-Ke Li
• Journal: Cell transplantation (Cell Transplant) Vol. 21 Issue 7 Pg. 1443-61 ( 2012) ISSN: 1555-3892 [Electronic] United States
• PMID: 22776314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proteome
• Heme Oxygenase-1
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Cell Adhesion
• Cell Movement
• Cells, Cultured
• Coronary Vessels (physiology)
• Endothelial Cells (cytology)
• Genetic Therapy
• Heme Oxygenase-1 (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Myocardial Infarction (metabolism, physiopathology, therapy)
• Myocardium (pathology)
• Myocytes, Cardiac (cytology)
• Neovascularization, Physiologic
• Phagocytosis
• Protein Array Analysis
• Proteome (metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Stem Cell Transplantation
• Stem Cells (cytology, metabolism)
• Ventricular Remodeling