Enhanced Cardiac Regenerative Ability of Stem Cells After Ischemia-Reperfusion Injury

Abstract

Background Micro ribonucleic acid (miR) dysregulation in the myocardium has been implicated in cardiac remodeling after injury or stress. Objectives This study sought to explore the role of miR in human CD34+ cell (hCD34+) dysfunction in vivo after transplantation into the myocardium under ischemia-reperfusion (I-R) conditions. Methods In response to inflammatory stimuli, the miR array profile of endothelial progenitor cells (EPC) was analyzed using a polymerase chain reaction-based miR microarray. MiR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF). We investigated the effect of miR-377 inhibition on hCD34+ cell angiogenic proteome profile, in vitro and on cardiac repair and function after I-R injury in immunodeficient mice. Results The miR array data from EPCs in response to inflammatory stimuli indicate changes in numerous miR with a robust decrease in miR-377. Human cardiac biopsies from HF patients showed significant increase in miR-377 expression compared to nonfailing control hearts. Proteome profile of hCD34+ cells transfected with miR-377 mimics showed significant decrease in proangiogenic proteins versus nonspecific control transfected cells. We also validated that serine/threonine kinase 35 is a target of miR-377 using a dual-luciferase reporter assay. In a mouse model of myocardial I-R, intramyocardial transplantation of miR-377-silenced hCD34+ cells in immunodeficient mice, promoting neovascularization (at 28 days, post-I-R) and lower interstitial fibrosis, leading to improved left ventricular (LV) function. Conclusions These findings indicate that HF increases miR-377 in the myocardium, which is detrimental to stem cell function, and transplantation of miR-377 knockdown hCD34+ cells into ischemic myocardium promoted their angiogenic ability, attenuating LV remodeling and cardiac fibrosis.

MicroRNA: A new therapeutic strategy for cardiovascular diseases

“…Further more, transplantation of miRNA-377 knockdown human CD34 cells into the ischemic mouse myocardium promoted cardiac repair and attenuated ventricular function. This study also identified that STK35 kinase is the direct target of miRNA 377 during MI [42]. These studies documented that miRNAs are important in regulating the pathological conditions of MI.…”

MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes

“…Bone marrow-derived macrophages (BMM) were isolated from the bone marrow of non-diabetic control (wild type) and diabetic (db/db) mice as described in our previous studies4445. In brief, BMM was isolated from mice by density-gradient centrifugation with Histopaque-1083 (Sigma).…”

“…MiR-126 mimic, miR-126 inhibitor and their respective nonspecific control (mirVana TM miRNA mimic negative control, Ambion, Thermo Fisher Scientific, U.S.A) were used for transfection as described previously44. Briefly, RAW 264.7 cells were seeded in 6-well plates and subjected to NG or HG conditions 48 hours prior to transfection.…”

MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1

“…Recently, we reported, that transplantation of miR-377 silenced hCD34 (+) cells promote neovascularization and improved left ventricular function in a mouse model of heart failure (HF) [10]. However, studies to show the participation of miRNAs in cardiac pyroptosis, specifically in DCM are limited.…”