title: The CD4(+) AT2R(+) T cell subpopulation improves post-infarction remodelling and restores cardiac function.
abstract: Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4(+) AT2R(+) cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4(+) AT2R(+) T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4(+) cells. CD4(+) AT2R(+) T cells within blood CD4(+) T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4(+) AT2R(+) T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4(+) AT2R(+) T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4(+) AT2R(+) cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4(+) AT2R(+) cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof.
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Skorska
authors.affiliation: Center for Cardiovascular Research and Department of Cardiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|University of Göttingen Medical School, Göttingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Haehling
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Cornelia A
authors.initials: CA
authors.lastname: Lux
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gaebel
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kleiner
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Klopsch
authors.affiliation: German Rheumatism Research Centre, Berlin, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.affiliation: Center for Cardiovascular Research (CCR) and Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Curato
authors.affiliation: Center for Cardiovascular Research (CCR) and Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Wassim
authors.initials: W
authors.lastname: Altarche-Xifró
authors.affiliation: Center for Cardiovascular Research (CCR) and Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Slavic
authors.affiliation: Center for Cardiovascular Research (CCR) and Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinhoff
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.|Clinical Stem Cell Research Center and Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Reference and Translation Centre for Cardiac Stem Cell Therapy (RTC)/Department of Cardiac Surgery, University of Rostock, Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: David
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002316:Cardiotonic Agents / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D006334:Heart Function Tests; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000097:blood; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D020257:Ventricular Remodeling
chemical_list: D002316:Cardiotonic Agents; D044139:Receptor, Angiotensin, Type 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
keywords: CD4+ lymphocytes; angiotensin II type 2 receptor; heart failure cardiac remodelling; myocardial infarction; renin angiotensin system