Mark E Pepin1, Concetta Schiano2, Marco Miceli3, Giuditta Benincasa4, Gelsomina Mansueto5, Vincenzo Grimaldi6, Andrea Soricelli7, Adam R Wende8, Claudio Napoli9. 1. Dept. of Pathology, Division of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, USA; Dept. of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, USA; Institüt für Experimentelle Kardiologie, Universitätsklinikum Heidelberg, Heidelberg, Germany. Electronic address: mark.pepin@med.uni-heidelberg.de. 2. Dept. of Advanced Medical and Surgical Sciences (DAMSS), Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy. Electronic address: concetta.schiano@unicampania.it. 3. IRCCS SDN, Via E. Gianturco, 113 - 80143, Naples, Italy. Electronic address: mmiceli@sdn-napoli.it. 4. Dept. of Advanced Medical and Surgical Sciences (DAMSS), Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy. Electronic address: giuditta.benincasa@unicampania.it. 5. Dept. of Advanced Medical and Surgical Sciences (DAMSS), Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy; Clinical Dept. of Internal Medicine and Specialistic Units, Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy. Electronic address: gelsomina.mansueto@unicampania.it. 6. Dept. of Advanced Medical and Surgical Sciences (DAMSS), Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy; IRCCS SDN, Via E. Gianturco, 113 - 80143, Naples, Italy. Electronic address: vincenzo.grimaldi@policliniconapoli.it. 7. IRCCS SDN, Via E. Gianturco, 113 - 80143, Naples, Italy; Dept of Exercise and Wellness Sciences, University of Naples Parthenope, Via Ammiraglio Ferdinando Acton, 38 - 80133 Naples, Italy. Electronic address: andrea.soricelli@uniparthenope.it. 8. Dept. of Pathology, Division of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, USA; Dept. of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, USA. Electronic address: adamwende@uabmc.edu. 9. Dept. of Advanced Medical and Surgical Sciences (DAMSS), Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy; IRCCS SDN, Via E. Gianturco, 113 - 80143, Naples, Italy; Clinical Dept. of Internal Medicine and Specialistic Units, Università Della Campania "Luigi Vanvitelli", P.za Miraglia, 2 - 80138, Naples, Italy. Electronic address: direzione.immunoematologia@unicampania.it.
Abstract
BACKGROUND: Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming. METHODS: In the current study, we quantified genome-wide DNA methylation of cultured human endothelial aortic cells (HAECs) via reduced-representation bisulfite sequencing (RRBS) following exposure to diabetic (250 mg/dL), pre-diabetic (125 mg/dL), or euglycemic (100 mg/dL) glucose concentrations for 72 h (n = 2). RESULTS: We discovered glucose-dependent methylation of genomic regions (DMRs) encompassing 2199 genes, with a disproportionate number found among genes associated with angiogenesis and nitric oxide (NO) signaling-related pathways. Multi-omics analysis revealed differential methylation and gene expression of VEGF (↑5.6% DMR, ↑3.6-fold expression), and NOS3 (↓20.3% DMR, ↓1.6-fold expression), nodal regulators of angiogenesis and NO signaling, respectively. CONCLUSION: In the current exploratory study, we examine glucose-dependent and dose-responsive alterations in endothelial DNA methylation to examine a putative epigenetic mechanism underlying diabetic vasculopathy. Specifically, we uncover the disproportionate glucose-dependent methylation and gene expression of VEGF and NO signaling cascades, a physiologic imbalance known to cause endothelial dysfunction in diabetes. We therefore hypothesize that epigenetic mechanisms encode a glycemic memory within endothelial cells.
BACKGROUND: Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming. METHODS: In the current study, we quantified genome-wide DNA methylation of cultured human endothelial aortic cells (HAECs) via reduced-representation bisulfite sequencing (RRBS) following exposure to diabetic (250 mg/dL), pre-diabetic (125 mg/dL), or euglycemic (100 mg/dL) glucose concentrations for 72 h (n = 2). RESULTS: We discovered glucose-dependent methylation of genomic regions (DMRs) encompassing 2199 genes, with a disproportionate number found among genes associated with angiogenesis and nitric oxide (NO) signaling-related pathways. Multi-omics analysis revealed differential methylation and gene expression of VEGF (↑5.6% DMR, ↑3.6-fold expression), and NOS3 (↓20.3% DMR, ↓1.6-fold expression), nodal regulators of angiogenesis and NO signaling, respectively. CONCLUSION: In the current exploratory study, we examine glucose-dependent and dose-responsive alterations in endothelial DNA methylation to examine a putative epigenetic mechanism underlying diabetic vasculopathy. Specifically, we uncover the disproportionate glucose-dependent methylation and gene expression of VEGF and NO signaling cascades, a physiologic imbalance known to cause endothelial dysfunction in diabetes. We therefore hypothesize that epigenetic mechanisms encode a glycemic memory within endothelial cells.
Authors: Filomena de Nigris; Francesco Cacciatore; Francesco P Mancini; Dino F Vitale; Gelsomina Mansueto; Francesco P D'Armiento; Concetta Schiano; Andrea Soricelli; Claudio Napoli Journal: JAMA Cardiol Date: 2018-12-01 Impact factor: 14.676
Authors: Mark E Pepin; Teresa Infante; Giuditta Benincasa; Concetta Schiano; Marco Miceli; Simona Ceccarelli; Francesca Megiorni; Eleni Anastasiadou; Giovanni Della Valle; Gerardo Fatone; Mario Faenza; Ludovico Docimo; Giovanni F Nicoletti; Cinzia Marchese; Adam R Wende; Claudio Napoli Journal: Front Genet Date: 2020-04-15 Impact factor: 4.599
Authors: Sara Andrade; Tiago Morais; Ionel Sandovici; Alexandre L Seabra; Miguel Constância; Mariana P Monteiro Journal: Front Endocrinol (Lausanne) Date: 2021-06-29 Impact factor: 5.555