title: Secretome of apoptotic peripheral blood cells (APOSEC) confers cytoprotection to cardiomyocytes and inhibits tissue remodelling after acute myocardial infarction: a preclinical study.
abstract: Heart failure following acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Our previous observation that injection of apoptotic peripheral blood mononuclear cell (PBMC) suspensions was able to restore long-term cardiac function in a rat AMI model prompted us to study the effect of soluble factors derived from apoptotic PBMC on ventricular remodelling after AMI. Cell culture supernatants derived from irradiated apoptotic peripheral blood mononuclear cells (APOSEC) were collected and injected as a single dose intravenously after myocardial infarction in an experimental AMI rat model and in a porcine closed chest reperfused AMI model. Magnetic resonance imaging (MRI) and echocardiography were used to quantitate cardiac function. Analysis of soluble factors present in APOSEC was performed by enzyme-linked immunosorbent assay (ELISA) and activation of signalling cascades in human cardiomyocytes by APOSEC in vitro was studied by immunoblot analysis. Intravenous administration of a single dose of APOSEC resulted in a reduction of scar tissue formation in both AMI models. In the porcine reperfused AMI model, APOSEC led to higher values of ejection fraction (57.0 vs. 40.5%, p < 0.01), a better cardiac output (4.0 vs. 2.4 l/min, p < 0.001) and a reduced extent of infarction size (12.6 vs. 6.9%, p < 0.02) as determined by MRI. Exposure of primary human cardiac myocytes with APOSEC in vitro triggered the activation of pro-survival signalling-cascades (AKT, Erk1/2, CREB, c-Jun), increased anti-apoptotic gene products (Bcl-2, BAG1) and protected them from starvation-induced cell death. Intravenous infusion of culture supernatant of apoptotic PBMC attenuates myocardial remodelling in experimental AMI models. This effect is probably due to the activation of pro-survival signalling cascades in the affected cardiomyocytes.
authors.affiliation: Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Lichtenauer
authors.forename: Michael
authors.initials: M
authors.lastname: Mildner
authors.forename: Konrad
authors.initials: K
authors.lastname: Hoetzenecker
authors.forename: Matthias
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Bruno Karl
authors.initials: BK
authors.lastname: Podesser
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sipos
authors.forename: Ervin
authors.initials: E
authors.lastname: Berényi
authors.forename: Martin
authors.initials: M
authors.lastname: Dworschak
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.forename: Mariann
authors.initials: M
authors.lastname: Gyöngyösi
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Ankersmit
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002469:Cell Separation; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology*; D019610:Cytoprotection / Q000502:physiology; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013552:Swine; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D017077:Culture Media, Conditioned