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1.
Eur J Clin Invest ; 54(3): e14135, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37991085

RESUMEN

BACKGROUND: Although mounting evidence supports that aberrant DNA methylation occurs in the hearts of patients with atrial fibrillation (AF), noninvasive epigenetic characterization of AF has not yet been defined. METHODS: We investigated DNA methylome changes in peripheral blood CD4+ T cells isolated from 10 patients with AF relative to 11 healthy subjects (HS) who were enrolled in the DIANA clinical trial (NCT04371809) via reduced-representation bisulfite sequencing (RRBS). RESULTS: An atrial-specific PPI network revealed 18 hub differentially methylated genes (DMGs), wherein ROC curve analysis revealed reasonable diagnostic performance of DNA methylation levels found within CDK5R1 (AUC = 0.76; p = 0.049), HSPG2 (AUC = 0.77; p = 0.038), WDFY3 (AUC = 0.78; p = 0.029), USP49 (AUC = 0.76; p = 0.049), GSE1 (AUC = 0.76; p = 0.049), AIFM1 (AUC = 0.76; p = 0.041), CDK5RAP2 (AUC = 0.81; p = 0.017), COL4A1 (AUC = 0.86; p < 0.001), SEPT8 (AUC = 0.90; p < 0.001), PFDN1 (AUC = 0.90; p < 0.01) and ACOT7 (AUC = 0.78; p = 0.032). Transcriptional profiling of the hub DMGs provided a significant overexpression of PSDM6 (p = 0.004), TFRC (p = 0.01), CDK5R1 (p < 0.001), HSPG2 (p = 0.01), WDFY3 (p < 0.001), USP49 (p = 0.004) and GSE1 (p = 0.021) in AF patients vs HS. CONCLUSIONS: CDK5R1, GSE1, HSPG2 and WDFY3 resulted the best discriminatory genes both at methylation and gene expression level. Our results provide several candidate diagnostic biomarkers with the potential to advance precision medicine in AF.


Asunto(s)
Fibrilación Atrial , Humanos , Metilación de ADN , Atrios Cardíacos , Análisis de Secuencia de ADN , Epigénesis Genética , Proteínas del Tejido Nervioso/genética , Proteínas de Ciclo Celular/genética , Proteínas Relacionadas con la Autofagia/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Ubiquitina Tiolesterasa/genética , Proteínas de Neoplasias/genética
2.
Matern Child Health J ; 28(4): 617-630, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38409452

RESUMEN

INTRODUCTION: The ability to identify early epigenetic signatures underlying the inheritance of cardiovascular risk, including trans- and intergenerational effects, may help to stratify people before cardiac symptoms occur. METHODS: Prospective and retrospective cohorts and case-control studies focusing on DNA methylation and maternal/paternal effects were searched in Pubmed from 1997 to 2023 by using the following keywords: DNA methylation, genomic imprinting, and network analysis in combination with transgenerational/intergenerational effects. RESULTS: Maternal and paternal exposures to traditional cardiovascular risk factors during critical temporal windows, including the preconceptional period or early pregnancy, may perturb the plasticity of the epigenome (mainly DNA methylation) of the developing fetus especially at imprinted loci, such as the insulin-like growth factor type 2 (IGF2) gene. Thus, the epigenome is akin to a "molecular archive" able to memorize parental environmental insults and predispose an individual to cardiovascular diseases onset in later life. Direct evidence for human transgenerational epigenetic inheritance (at least three generations) of cardiovascular risk is lacking but it is supported by epidemiological studies. Several blood-based association studies showed potential intergenerational epigenetic effects (single-generation studies) which may mediate the transmittance of cardiovascular risk from parents to offspring. DISCUSSION: In this narrative review, we discuss some relevant examples of trans- and intergenerational epigenetic associations with cardiovascular risk. In our perspective, we propose three network-oriented approaches which may help to clarify the unsolved issues regarding transgenerational epigenetic inheritance of cardiovascular risk and provide potential early biomarkers for primary prevention.


Asunto(s)
Enfermedades Cardiovasculares , Epigénesis Genética , Masculino , Embarazo , Femenino , Humanos , Enfermedades Cardiovasculares/genética , Estudios Retrospectivos , Estudios Prospectivos , Metilación de ADN
3.
Int J Mol Sci ; 25(5)2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38474301

RESUMEN

Familial dilated cardiomyopathy (DCM) is among the leading indications for heart transplantation. DCM alters the transcriptomic profile. The alteration or activation/silencing of physiologically operating transcripts may explain the onset and progression of this pathological state. The mediator complex (MED) plays a fundamental role in the transcription process. The aim of this study is to investigate the MED subunits, which are altered in DCM, to identify target crossroads genes. RNA sequencing allowed us to identify specific MED subunits that are altered during familial DCM, transforming into human myocardial samples. N = 13 MED subunits were upregulated and n = 7 downregulated. MED9 alone was significantly reduced in patients compared to healthy subjects (HS) (FC = -1.257; p < 0.05). Interestingly, we found a short MED9 isoform (MED9s) (ENSG00000141026.6), which was upregulated when compared to the full-transcript isoform (MED9f). Motif identification analysis yielded several significant matches (p < 0.05), such as GATA4, which is downregulated in CHD. Moreover, although the protein-protein interaction network showed FOG2/ZFPM2, FOS and ID2 proteins to be the key interacting partners of GATA4, only FOG2/ZFPM2 overexpression showed an interaction score of "high confidence" ≥ 0.84. A significant change in the MED was observed during HF. For the first time, the MED9 subunit was significantly reduced between familial DCM and HS (p < 0.05), showing an increased MED9s isoform in DCM patients with respect to its full-length transcript. MED9 and GATA4 shared the same sequence motif and were involved in a network with FOG2/ZFPM2, FOS, and ID2, proteins already implicated in cardiac development.


Asunto(s)
Cardiomiopatía Dilatada , Complejo Mediador , Humanos , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Trasplante de Corazón , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Complejo Mediador/genética , Complejo Mediador/metabolismo
4.
Am Heart J ; 258: 96-113, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36565787

RESUMEN

A major gap in diagnosis, classification, risk stratification, and prediction of therapeutic response exists in pulmonary arterial hypertension (PAH), driven in part by a lack of functional biomarkers that are also disease-specific. In this regard, leveraging big data-omics analyses using innovative approaches that integrate network medicine and machine learning correlated with clinically useful indices or risk stratification scores is an approach well-positioned to advance PAH precision medicine. For example, machine learning applied to a panel of 48 cytokines, chemokines, and growth factors could prognosticate PAH patients with immune-dominant subphenotypes at elevated or low-risk for mortality. Here, we discuss strengths and weaknesses of the most current studies evaluating omics-derived biomarkers in PAH. Progress in this field is offset by studies with small sample size, pervasive limitations in bioinformatics, and lack of standardized methods for data processing and interpretation. Future success in this field, in turn, is likely to hinge on mechanistic validation of data outputs in order to couple functional biomarker data with target-specific therapeutics in clinical practice.


Asunto(s)
Hipertensión Arterial Pulmonar , Humanos , Hipertensión Arterial Pulmonar/diagnóstico , Biomarcadores , Aprendizaje Automático , Medicina de Precisión , Factores de Riesgo
5.
J Transl Med ; 21(1): 273, 2023 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-37085802

RESUMEN

Early in the COVID-19 pandemic, it emerged that the risk of severe outcomes was greater in patients with co-morbidities, including cancer. The huge effort undertaken to fight the pandemic, affects the management of cancer care, influencing their outcome. Despite the high fatality rate of COVID-19 disease in cancer patients, rare cases of temporary or prolonged clinical remission from cancers after SARS-CoV-2 infection have been reported. We have reviewed sixteen case reports of COVID-19 disease with spontaneous cancer reduction of progression. Fourteen cases of remission following viral infections and two after anti-SARS-CoV-2 vaccination. The immune response to COVID-19, may be implicated in both tumor regression, and progression. Specifically, we discuss potential mechanisms which include oncolytic and priming hypotheses, that may have contributed to the cancer regression in these cases and could be useful for future options in cancer treatment.


Asunto(s)
COVID-19 , Neoplasias , Humanos , Pandemias , SARS-CoV-2 , Neoplasias/complicaciones , Neoplasias/terapia
6.
Cell ; 132(3): 397-409, 2008 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-18267072

RESUMEN

Adenoviruses are used extensively as gene transfer agents, both experimentally and clinically. However, targeting of liver cells by adenoviruses compromises their potential efficacy. In cell culture, the adenovirus serotype 5 fiber protein engages the coxsackievirus and adenovirus receptor (CAR) to bind cells. Paradoxically, following intravascular delivery, CAR is not used for liver transduction, implicating alternate pathways. Recently, we demonstrated that coagulation factor (F)X directly binds adenovirus leading to liver infection. Here, we show that FX binds to the Ad5 hexon, not fiber, via an interaction between the FX Gla domain and hypervariable regions of the hexon surface. Binding occurs in multiple human adenovirus serotypes. Liver infection by the FX-Ad5 complex is mediated through a heparin-binding exosite in the FX serine protease domain. This study reveals an unanticipated function for hexon in mediating liver gene transfer in vivo.


Asunto(s)
Adenovirus Humanos/fisiología , Proteínas de la Cápside/metabolismo , Factor X/metabolismo , Hígado/virología , Transducción Genética , Internalización del Virus , Adenovirus Humanos/química , Adenovirus Humanos/clasificación , Animales , Proteínas de la Cápside/química , Proteínas Portadoras/metabolismo , Microscopía por Crioelectrón , Factor X/química , Hepatocitos/virología , Humanos , Imagenología Tridimensional , Ratones , Ratones Transgénicos , Modelos Moleculares , Filogenia , Unión Proteica/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , Resonancia por Plasmón de Superficie , Warfarina/farmacología
7.
J Thromb Thrombolysis ; 55(1): 51-59, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36371754

RESUMEN

Only a percentage of COVID-19 patients develop thrombotic complications. We hypothesized that genetic profiles may explain part of the inter-individual differences. Our goal was to evaluate the genotypic distribution of targeted DNA polymorphisms in COVID-19 patients complicated (PE+) or not (PE-) by pulmonary embolism. We designed a retrospective observational study enrolling N = 94 consecutive patients suffering severe COVID-19 with pulmonary embolism (PE+, N = 47) or not (PE-, N = 47) during hospitalization. A panel of N = 13 prothrombotic DNA polymorphisms (FV R506Q and H1299R, FII G20210A, MTHFR C677T and A1298C, CBS 844ins68, PAI-1 4G/5G, GPIIIa HPA-1 a/b, ACE I/D, AGT T9543C, ATR-1 A1166C, FGB - 455G > A, FXIII103G > T) and N = 2 lipid metabolism-related DNA polymorphisms (APOE T 112C and T158C) were investigated using Reverse Dot Blot technique. Then, we investigated possible associations between genotypic subclasses and demographic, clinical, and laboratory parameters including age, obesity, smoking, pro-inflammatory cytokines, drug therapy, and biomarkers of thrombotic risk such as D-dimer (DD). We found that 58.7% of PE+ had homozygous mutant D/D genotype at ACE I/D locus vs. PE- (40.4%) and 87% of PE+ had homozygous mutant C/C genotype at APOE T158C locus vs. PE- (68.1%). In PE+ group, DD levels were significantly higher in D/D and I/D genotypes at ACE I/D locus (P = 0.00066 and P = 0.00023, respectively) and in C/C and T/C genotypes at APOE T158C locus (P = 1.6e-06 and P = 0.0012, respectively) than PE- group. For the first time, we showed significant associations between higher DD levels and ACE I/D and APOE T158C polymorphisms in PE+ vs. PE- patients suggesting potential useful biomarkers of poor clinical outcome.


Asunto(s)
COVID-19 , Embolia Pulmonar , Trombosis , Humanos , COVID-19/complicaciones , COVID-19/genética , Embolia Pulmonar/genética , Biomarcadores , Apolipoproteínas E , ADN
8.
Int J Mol Sci ; 24(8)2023 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37108672

RESUMEN

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.


Asunto(s)
Enfermedades Cardiovasculares , Vesículas Extracelulares , Neoplasias , Humanos , Células Endoteliales/patología , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Neoplasias/genética , Neoplasias/patología , Enfermedades Cardiovasculares/patología , Epigénesis Genética , Microambiente Tumoral/genética
9.
Neurobiol Dis ; 164: 105611, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34995755

RESUMEN

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.


Asunto(s)
Depresión/metabolismo , Hemorragias Intracraneales/metabolismo , Microglía/metabolismo , Dolor/metabolismo , Transducción de Señal/fisiología , Tálamo/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/etiología , Hemorragias Intracraneales/complicaciones , Subunidad 1 del Complejo Mediador/metabolismo , Ratones , Actividad Motora/fisiología , Dolor/etiología , Ratas Sprague-Dawley , Receptor trkB/metabolismo
10.
Cardiovasc Diabetol ; 21(1): 146, 2022 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-35932065

RESUMEN

BACKGROUND: High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control. OBJECTIVES: We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts. METHODS: We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis. RESULTS: GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression. CONCLUSION: Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT03546062.


Asunto(s)
Diabetes Mellitus , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Fibrosis , Hemoglobina Glucada/metabolismo , Humanos , Fragmentos de Péptidos , Peptidil-Dipeptidasa A
11.
J Vasc Res ; 59(1): 61-68, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34535602

RESUMEN

Increasing evidence suggests that maternal cholesterol represents an important risk factor for atherosclerotic disease in offspring already during pregnancy, although the underlying mechanisms have not yet been elucidated. Eighteen human fetal aorta samples were collected from the spontaneously aborted fetuses of normal cholesterolemic and hypercholesterolemic mothers. Maternal total cholesterol levels were assessed during hospitalization. DNA methylation profiling of the whole SREBF2 gene CpG island was performed (p value <0.05). The Mann-Whitney U test was used for comparison between the 2 groups. For the first time, our study revealed that in fetal aortas obtained from hypercholesterolemic mothers, the SREBF2 gene shows 4 significant differentially hypermethylated sites in the 5'UTR-CpG island. This finding indicates that more effective long-term primary cardiovascular prevention programs need to be designed for the offspring of mothers with hypercholesterolemia. Further studies should be conducted to clarify the epigenetic mechanisms underlying the association between early atherogenesis and maternal hypercholesterolemia during pregnancy.


Asunto(s)
Aorta/metabolismo , Metilación de ADN , Epigénesis Genética , Hipercolesterolemia/genética , Complicaciones del Embarazo/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Aorta/embriología , Biomarcadores/sangre , Estudios de Casos y Controles , Colesterol/sangre , Epigenoma , Femenino , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Edad Gestacional , Humanos , Hipercolesterolemia/sangre , Embarazo , Complicaciones del Embarazo/sangre , Mapas de Interacción de Proteínas
12.
Pharmacol Res ; 175: 106039, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34929299

RESUMEN

Epidemiological evidence shows that diabetic patients have an increased cancer risk and a higher mortality rate. Glucose could play a central role in metabolism and growth of many tumor types, and this possible mechanism is supported by the high rate of glucose demand and uptake in cancer. Thus, growing evidence suggests that hyperglycemia contributes to cancer progression but also to its onset. Many mechanisms underlying this association have been hypothesized, such as insulin resistance, hyperinsulinemia, and increased inflammatory processes. Inflammation is a common pathophysiological feature in both diabetic and oncological patients, and inflammation linked to high glucose levels sensitizes microenvironment to tumorigenesis, promoting the development of malignant lesions by altering and sustaining a pathological condition in tissues. Glycemic control is the first goal of antidiabetic therapy, and glucose level reduction has also been associated with favorable outcomes in cancer. Here, we describe key events in carcinogenesis focusing on hyperglycemia as supporter in tumor progression and in particular, related to the role of a specific hypoglycemic drug class, sodium-glucose linked transporters (SGLTs). We also discuss the use of SGLT2 inhibitors as a novel potential cancer therapy. Our meta-analysis showed that SGLT-2 inhibitors were significantly associated with an overall reduced risk of cancer as compared to placebo (RR = 0.35, CI 0.33-0.37, P = 0. 00) with a particular effectiveness for dapaglifozin and ertuglifozin (RR = 0. 06, CI 0. 06-0. 07 and RR = 0. 22, CI 0. 18-0. 26, respectively). Network Medicine approaches may advance the possible repurposing of these drugs in patients with concomitant diabetes and cancer.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Reposicionamiento de Medicamentos , Epigénesis Genética , Glucosa/metabolismo , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/epidemiología , Hiperglucemia/genética , Incidencia , Neoplasias/epidemiología , Neoplasias/etiología , Neoplasias/genética , Ensayos Clínicos Controlados Aleatorios como Asunto
13.
Pharmacol Res ; 184: 106448, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36096423

RESUMEN

This study aimed at investigating the SGLT2 expression in human cardiomyocytes. Human studies evaluating cardiomyocyte SGLT2s expression are limited. To better clarify this issue, SGLT2 protein expression was assessed in human hearts of diabetic and non-diabetic patients, and in AC16 human cardiomyocyte cell line. A prospective study with a follow-up of patients who underwent their first heart transplant (HTX) was performed. Explanted heart, basal (1 week after HTX), and final (48 weeks after HTX) endomyocardial biopsies (EMBs) from patients were evaluated for SGLT2 occurrence in cardiomyocyte with immunohistochemistry, immunofluorescence and SGLT2 quantization with both real-time reverse transcription-polymerase chain reaction and Western blot analysis. The immunofluorescence co-localization of SGLT2 in cardiomyocyte evidenced that an increased expression in the explanted heart from diabetic patients compared to non-diabetic (p < 0.001). In all final EMBs from diabetic patients, the expression of SGLT2 in cardiomyocyte was increased compared to non-diabetic (p < 0.01). This evidence was confirmed by Western blot analysis of SGLT2 protein. In addition, PCR analysis revealed very low mRNA levels in basal EMBs from diabetic and non-diabetic patients (p = NS), whereas final EMBs from diabetic patients showed higher SGLT2 mRNA levels in diabetic compared to non-diabetic patients (p < 0.05). Cultured human cardiomyocytes exposed to high-glucose showed increased expression of SGLT2 protein compared to cells exposed to normal glucose (p < 0.05). The presence of SGLT2 in cardiomyocytes supports the hypothesis of SGLT2i-mediated impact on metabolic pathways within cardiomyocytes. Moreover, metabolic disorders linked to diabetes may lead promptly to upregulation of SGLT2 levels in human cardiomyocytes.


Asunto(s)
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Humanos , Miocitos Cardíacos/metabolismo , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sodio/metabolismo , Transportador 2 de Sodio-Glucosa/genética , Transportador 2 de Sodio-Glucosa/metabolismo
14.
Exp Cell Res ; 400(2): 112485, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33515594

RESUMEN

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.


Asunto(s)
Aorta/metabolismo , Metilación de ADN , Endotelio Vascular/metabolismo , Epigénesis Genética , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/farmacología , Hiperglucemia/fisiopatología , Aorta/efectos de los fármacos , Aorta/patología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Humanos , Regiones Promotoras Genéticas
15.
Can J Physiol Pharmacol ; 100(2): 93-106, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35112597

RESUMEN

Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.


Asunto(s)
Cardiotónicos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Adipoquinas/metabolismo , Antiinflamatorios , Antifibróticos , Hemodinámica/efectos de los fármacos , Humanos , Glomérulos Renales/metabolismo , Miocitos Cardíacos/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos
16.
Eur Respir J ; 57(6)2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33214212

RESUMEN

Epigenetic mechanisms represent potential molecular routes which could bridge the gap between genetic background and environmental risk factors contributing to the pathogenesis of pulmonary diseases. In patients with COPD, asthma and pulmonary arterial hypertension (PAH), there is emerging evidence of aberrant epigenetic marks, mainly including DNA methylation and histone modifications which directly mediate reversible modifications to the DNA without affecting the genomic sequence. Post-translational events and microRNAs can be also regulated epigenetically and potentially participate in disease pathogenesis. Thus, novel pathogenic mechanisms and putative biomarkers may be detectable in peripheral blood, sputum, nasal and buccal swabs or lung tissue. Besides, DNA methylation plays an important role during the early phases of fetal development and may be impacted by environmental exposures, ultimately influencing an individual's susceptibility to COPD, asthma and PAH later in life. With the advances in omics platforms and the application of computational biology tools, modelling the epigenetic variability in a network framework, rather than as single molecular defects, provides insights into the possible molecular pathways underlying the pathogenesis of COPD, asthma and PAH. Epigenetic modifications may have clinical applications as noninvasive biomarkers of pulmonary diseases. Moreover, combining molecular assays with network analysis of epigenomic data may aid in clarifying the multistage transition from a "pre-disease" to "disease" state, with the goal of improving primary prevention of lung diseases and its subsequent clinical management.We describe epigenetic mechanisms known to be associated with pulmonary diseases and discuss how network analysis could improve our understanding of lung diseases.


Asunto(s)
Asma , MicroARNs , Asma/genética , Metilación de ADN , Epigénesis Genética , Epigenómica , Humanos , MicroARNs/metabolismo , Medicina de Precisión
17.
Cardiovasc Diabetol ; 20(1): 99, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33962629

RESUMEN

RATIONALE: About 50% of hospitalized coronavirus disease 2019 (COVID-19) patients with diabetes mellitus (DM) developed myocardial damage. The mechanisms of direct SARS-CoV-2 cardiomyocyte infection include viral invasion via ACE2-Spike glycoprotein-binding. In DM patients, the impact of glycation of ACE2 on cardiomyocyte invasion by SARS-CoV-2 can be of high importance. OBJECTIVE: To evaluate the presence of SARS-CoV-2 in cardiomyocytes from heart autopsy of DM cases compared to Non-DM; to investigate the role of DM in SARS-COV-2 entry in cardiomyocytes. METHODS AND RESULTS: We evaluated consecutive autopsy cases, deceased for COVID-19, from Italy between Apr 30, 2020 and Jan 18, 2021. We evaluated SARS-CoV-2 in cardiomyocytes, expression of ACE2 (total and glycosylated form), and transmembrane protease serine protease-2 (TMPRSS2) protein. In order to study the role of diabetes on cardiomyocyte alterations, independently of COVID-19, we investigated ACE2, glycosylated ACE2, and TMPRSS2 proteins in cardiomyocytes from DM and Non-DM explanted-hearts. Finally, to investigate the effects of DM on ACE2 protein modification, an in vitro glycation study of recombinant human ACE2 (hACE2) was performed to evaluate the effects on binding to SARS-CoV-2 Spike protein. The authors included cardiac tissue from 97 autopsies. DM was diagnosed in 37 patients (38%). Fourth-seven out of 97 autopsies (48%) had SARS-CoV-2 RNA in cardiomyocytes. Thirty out of 37 DM autopsy cases (81%) and 17 out of 60 Non-DM autopsy cases (28%) had SARS-CoV-2 RNA in cardiomyocytes. Total ACE2, glycosylated ACE2, and TMPRSS2 protein expressions were higher in cardiomyocytes from autopsied and explanted hearts of DM than Non-DM. In vitro exposure of monomeric hACE2 to 120 mM glucose for 12 days led to non-enzymatic glycation of four lysine residues in the neck domain affecting the protein oligomerization. CONCLUSIONS: The upregulation of ACE2 expression (total and glycosylated forms) in DM cardiomyocytes, along with non-enzymatic glycation, could increase the susceptibility to COVID-19 infection in DM patients by favouring the cellular entry of SARS-CoV2.


Asunto(s)
Enzima Convertidora de Angiotensina 2/biosíntesis , COVID-19/metabolismo , Diabetes Mellitus/metabolismo , Miocitos Cardíacos/metabolismo , SARS-CoV-2/metabolismo , Anciano , Secuencia de Aminoácidos , Autopsia , COVID-19/epidemiología , COVID-19/patología , Estudios de Cohortes , Diabetes Mellitus/patología , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/patología , Unión Proteica/fisiología , Estructura Secundaria de Proteína
18.
Curr Opin Cardiol ; 36(3): 295-300, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33605616

RESUMEN

PURPOSE OF REVIEW: Cardiovascular diseases (CVDs) are typically caused by multifactorial events including mutations in a large number of genes. Epigenetic-derived modifications in the cells are normal but can be amended by aging, lifestyle, and exposure to toxic substances. Major epigenetic modifications are DNA methylation, histone modification, chromatin remodeling as well as the noncoding RNAs. These pivotal players are involved in the epigenetic-induced modifications observed during CVDs. Nevertheless, despite impressive efforts capitalized in epigenetic research in the last 50 years, clinical applications are still not satisfactory. RECENT FINDINGS: Briefly, we present some of the recent steps forward in the epigenetic studies of CVDs. There is an increased appreciation for the contribution of epigenetic alterations in the development of CVDs. Now, we have novel epigenetic biomarkers and therapeutic trials with the use of statins, metformin, and some compounds affecting epigenetic pathways including a BET inhibitor apabetalone. The new knowledge of epigenetic regulation is also discussed in the light of precision medicine of CVDs. SUMMARY: Epigenetic studies of CVDs have the promise to yield both mechanistic insights as well as adjunct treatments (repurposed drugs and apabetalone). The overall concept of precision medicine is not widely recognized in routine medical practice and the so-called reductionist approach remains the most used way to treat CVD patients.


Asunto(s)
Enfermedades Cardiovasculares , Epigénesis Genética , Enfermedades Cardiovasculares/genética , Metilación de ADN , Humanos , Medicina de Precisión , ARN no Traducido
19.
Clin Transplant ; 35(8): e14306, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33792965

RESUMEN

Current management of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) lacks immunosuppressant drugs able to block the host immune response toward the graft antigens. Novel treatments may include epigenetic compounds (epidrugs) some of which have been yet approved by the Food and Drugs Administration for the treatment of specific blood malignancies. The most investigated in clinical trials for allo-HSCT are DNA demethylating agents (DNMTi), such as azacitidine (Vidaza) and decitabine (Dacogen) as well as histone deacetylases inhibitors (HDACi), such as vorinostat (Zolinza) and panobinostat (Farydak). Indeed, azacitidine monotherapy before allo-HSCT may reduce the conventional chemotherapy-related complications, whereas it may reduce relapse risk and death after allo-HSCT. Besides, a decitabine-containing conditioning regimen could protect against graft versus host disease (GVHD) and respiratory infections after allo-HSCT. Regarding HDACi, the addition of vorinostat and panobinostat to the conditioning regimen after allo-HSCT seems to reduce the incidence of acute GVHD. Furthermore, panobinostat alone or in combination with low-dose decitabine may reduce the relapse rate in high-risk patients with acute myeloid leukemia patients after allo-HSCT. We discuss the phase 1 and 2 clinical trials evaluating the possible beneficial effects of repurposing specific epidrugs which may guide personalized therapy in the setting of allo-HSCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Epigénesis Genética , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Medicina de Precisión , Trasplante Homólogo
20.
Eur Heart J Suppl ; 23(Suppl C): C184-C195, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34456645

RESUMEN

This ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri) position paper aims to analyse the complex action of sodium-glucose co-transporter 2 inhibitors at the level of the kidney and cardiovascular system, focusing on the effect that these molecules have shown in the prevention and treatment of heart failure in diabetic and non-diabetic subjects. The goal was pursued by comparing the data generated with pathophysiology studies and with multicentre controlled studies in large populations. In accordance with the analysis carried out in the document, the following recommendations are issued: (i) canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are molecules recommended for the prevention of heart failure hospitalizations in type 2 diabetic subjects; (ii) canagliflozin and dapagliflozin are recommended for the prevention of heart failure hospitalizations in type 2 diabetic subjects with severe chronic kidney disease, dapagliflozin proved to be safe and effective also in diabetic subjects; and (iii) dapagliflozin and empagliflozin are recommended to reduce the combined risk of heart failure and cardiovascular death in diabetic and non-diabetic subjects with heart failure and reduced ejection fraction.

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