Cardiac Aging Is Promoted by Pseudohypoxia Increasing p300-Induced Glycolysis.

Autor: Serio S; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy (S.S., G.C.)., Pagiatakis C; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)., Musolino E; Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)., Felicetta A; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)., Carullo P; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)., Laura Frances J; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)., Papa L; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)., Rozzi G; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.)., Salvarani N; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Institute of Genetic and Biomedical Research, UOS of Milan, National Research Council of Italy (N.S.)., Miragoli M; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Department of Medicine and Surgery, University of Parma, Italy (M.M.)., Gornati R; Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)., Bernardini G; Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.)., Condorelli G; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy (S.S., G.C.)., Papait R; Department of Cardiovascular Medicine, IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (MI), Italy (S.S., C.P., A.F., P.C., J.L.F., L.P., G.R., N.S., M.M., G.C., R.P.).; Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100, Varese, Italy (C.P., E.M., R.G., G.B., R.P.).
Jazyk: angličtina
Zdroj: Circulation research [Circ Res] 2023 Sep 29; Vol. 133 (8), pp. 687-703. Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1161/CIRCRESAHA.123.322676
Abstrakt: Background: Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition.
Methods: To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart, we cross-compared epigenomic, transcriptomic, and metabolomic data from mice of different ages. In addition, the role of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB binding protein) in cardiac aging was investigated using a specific inhibitor of this histone acetyltransferase enzyme.
Results: We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of Hk2 -a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O 2 levels, via increased activity of P300/CBP. Pharmacological inhibition of this transcriptional coactivator before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline.
Conclusions: Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.
Competing Interests: Disclosures None.
Databáze: MEDLINE
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