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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 ?-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.

SUBMITTER: Limana F

PROVIDER: S-EPMC3808142 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Transcriptional profiling of HMGB1-induced myocardial repair identifies a key role for Notch signaling.

Limana Federica F Esposito Grazia G Fasanaro Pasquale P Foglio Eleonora E Arcelli Diego D Voellenkle Christine C Di Carlo Anna A Avitabile Daniele D Martelli Fabio F Russo Matteo Antonio MA Pompilio Giulio G Germani Antonia A C Capogrossi Maurizio M

Molecular therapy : the journal of the American Society of Gene Therapy 20130613 10

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. Functio ...[more]

PMID: 23760446

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Project description:BackgroundType 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism.ObjectivesWe aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease.MethodsWe combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy.ResultsT2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D.ConclusionsOur data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS.Trial registrationURL: https://www.Clinicaltrialsgov ; Unique Identifier: NCT01862237.

Dataset Information

Transcriptional profiling of HMGB1-induced myocardial repair identifies a key role for Notch signaling.

Publications

Transcriptional profiling of HMGB1-induced myocardial repair identifies a key role for Notch signaling.

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