title: Transcriptional profiling of HMGB1-induced myocardial repair identifies a key role for Notch signaling.
abstract: Exogenous high-mobility group box 1 protein (HMGB1) administration to the mouse heart, during acute myocardial infarction (MI), results in cardiac regeneration via resident c-kit(+) cell (CPC) activation. Aim of the present study was to identify the molecular pathways involved in HMGB1-induced heart repair. Gene expression profiling was performed to identify differentially expressed genes in the infarcted and bordering regions of untreated and HMGB1-treated mouse hearts, 3 days after MI. Functional categorization of the transcripts, accomplished using Ingenuity Pathway Analysis software (IPA), revealed that genes involved in tissue regeneration, that is, cardiogenesis, vasculogenesis and angiogenesis, were present both in the infarcted area and in the peri-infarct zone; HMGB1 treatment further increased the expression of these genes. IPA revealed the involvement of Notch signaling pathways in HMGB1-treated hearts. Importantly, HMGB1 determined a 35 and 58% increase in cardiomyocytes and CPCs expressing Notch intracellular cytoplasmic domain, respectively. Further, Notch inhibition by systemic treatment with the γ-secretase inhibitor DAPT, which blocked the proteolytic activation of Notch receptors, reduced the number of CPCs, their proliferative fraction, and cardiomyogenic differentiation in HMGB1-treated infarcted hearts. The present study gives insight into the molecular processes involved in HMGB1-mediated cardiac regeneration and indicates Notch signaling as a key player.
authors.affiliation: Laboratorio di Patologia Cellulare e Molecolare, San Raffaele Pisana, Istituto di Ricovero e Cura a Carattere Scientifico, Rome-IRCCS, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Limana
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fasanaro
authors.forename: Eleonora
authors.initials: E
authors.lastname: Foglio
authors.forename: Diego
authors.initials: D
authors.lastname: Arcelli
authors.forename: Christine
authors.initials: C
authors.lastname: Voellenkle
authors.forename: Anna
authors.initials: A
authors.lastname: Di Carlo
authors.forename: Daniele
authors.initials: D
authors.lastname: Avitabile
authors.forename: Fabio
authors.initials: F
authors.lastname: Martelli
authors.forename: Matteo Antonio
authors.initials: MA
authors.lastname: Russo
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.forename: Antonia
authors.initials: A
authors.lastname: Germani
authors.forename: Maurizio
authors.initials: M
authors.lastname: C Capogrossi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D051880:Receptors, Notch