Epigenetic remodeling in heart failure with preserved ejection fraction

PURPOSE OF REVIEW In this review, we critically address the role of epigenetic processing and its therapeutic modulation in heart failure with preserved ejection fraction (HFpEF). RECENT FINDINGS HFpEF associates with a poor prognosis and the identification of novel molecular targets and therapeutic approaches are in high demand. Emerging evidence indicates a key involvement of epigenetic signals in the regulation of transcriptional programs underpinning features of HFpEF. The growing understanding of chromatin dynamics has led to the development of selective epigenetic drugs able to reset transcriptional changes thus delaying or preventing the progression toward HFpEF. Epigenetic information in the setting of HFpEF can be employed to: (i) dissect novel epigenetic networks and chromatin marks contributing to HFpEF; (ii) unveil circulating and cell-specific epigenetic biomarkers; (iii) build predictive models by using computational epigenetics and deep machine learning; (iv) develop new chromatin modifying drugs for personalized management of HFpEF. SUMMARY Acquired epigenetic signatures during the lifetime can contribute to derail molecular pathways involved in HFpEF. A scrutiny investigation of the individual epigenetic landscape will offer opportunities to develop personalized epigenetic biomarkers and therapies to fight HFpEF in the decades to come

Bilateral Anterior Ischaemic Optic Neuropathy in a Child on Continuous Peritoneal Dialysis : Case report and literature review

Non-arteritic anterior ischaemic optic neuropathy (NAION) is a serious complication of continuous peritoneal dialysis (CPD) which can lead to poor vision and blindness. We report a five-year-old girl who had undergone a bilateral nephrectomy at the age of one year and was on home CPD. She was referred to the Paediatric Ophthalmology Unit of Sultan Qaboos University Hospital, Muscat, Oman, in 2013 with acute bilateral vision loss, preceded by a three-day history of poor oral intake. At presentation, the patient had severe systemic hypotension. An ophthalmological examination revealed severe bilateral visual impairment and NAION. She was treated with intravenous methylprednisolone and normal saline boluses. At a five-month follow-up, the visual acuity of the right eye had improved but vision in the left eye remained the same. Acute bilateral blindness due to NAION while on CPD is a rare condition in childhood. Paediatricians should be aware of this complication in order to ensure prompt management.Keywords:

Epi-Drugs in Heart Failure

Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure

Inflammation in Metabolic Cardiomyopathy

Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type

Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature

Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress

Genetic deletion of hepatic NCOR1 protects from atherosclerosis by promoting alternative bile acid-metabolism and sterol excretion

BACKGROUND The nuclear receptor corepressor 1 (NCOR1) plays an important role in the regulation of gene expression in immunometabolic conditions by connecting chromatin-modifying enzymes, coregulators and transcription factors. NCOR1 has been shown to be involved in cardiometabolic diseases. Recently, we demonstrated that the deletion of macrophage NCOR1 aggravates atherosclerosis by promoting CD36-triggered foam cell formation via PPARG derepression. PURPOSE Since NCOR1 modulates the function of several key regulators involved in hepatic lipid and bile acid metabolism, we hypothesized that its deletion in hepatocytes alters lipid metabolism and atherogenesis. METHODS To test this hypothesis, we generated hepatocyte-specific Ncor1 knockout mice on a Ldlr-/- background. Besides assessing the progression of the disease in thoracoabdominal aortae en face, we analyzed hepatic cholesterol and bile acid metabolism at expression and functional levels. RESULTS Our data demonstrate that liver-specific Ncor1 knockout mice on an atherosclerosis-prone background develop less atherosclerotic lesions than controls. Interestingly, under chow diet, plasma cholesterol levels of liver-specific Ncor1 knockout mice were slightly higher compared to control, but strongly reduced compared to control mice after feeding them an atherogenic diet for 12 weeks. Moreover, the hepatic cholesterol content was decreased in liver-specific Ncor1 knockout compared to control mice. Our mechanistic data revealed that NCOR1 reprograms the synthesis of bile acids towards the alternative pathway, which in turn reduce bile hydrophobicity and enhances fecal cholesterol excretion. CONCLUSIONS Our data suggest that hepatic Ncor1 deletion in mice decreases atherosclerosis development by reprograming bile acid metabolism and enhancing fecal cholesterol excretion

Endothelial SIRT6 deficiency promotes arterial thrombosis in mice

OBJECTIVE Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD$^{+}$-dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways. APPROACH AND RESULTS Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6$^{-/-}$ mice as compared to Sirt6$^{fl/fl}$ controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF-α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown. CONCLUSIONS Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis

Epigenetic control of angiogenic response in diabetes

Introduction and aim of thesis: Type 2 diabetes (T2D) is a major cause of disability due to the occurrence of micro and macrovascular complications. Patients who experience vascular complications are not only at very risk of mortality, but they are also exposed to a concrete risk of social and mental effects (i.e., depression, anxiety) which further dampen quality of life. Among the constellation of cardiovascular comorbidities, diabetes shows the highest association with peripheral artery disease (PAD), a condition characterized by atherosclerotic lesions, reduced blood supply and chronic ischemia of the lower extremities. T2D is highly prevalent in patients with PAD and has been co-diagnosed in nearly 40% of all PAD patients. Despite advances in revascularization strategies, the rate of limb amputation due to chronic limb ischemia remains high and associates with cardiovascular morbidity in diabetic patients. In this perspective, strategies that promote vascularization can be considered as a novel therapeutic option in diabetic patients with PAD. Epigenetic changes, defined as plastic chemical modifications of DNA/histone complexes – have shown to modulate gene activity by modifying chromatin accessibility to transcription factors. Whether epigenetic modifications affect angiogenesis and post-ischemic vascularization remains to be elucidated. The mammalian methyltransferase SETD7 has emerged as a pivotal modulator of gene expression by its ability to induce histone methylation. Chromatin changes induced by SETD7 foster transcriptional programs implicated in endothelial inflammation and oxidative stress. By this background, in the present thesis I investigate whether epigenetic signals induced by SETD7 affect angiogenic properties of endothelial cells in the setting of diabetes. Main research tasks: To investigate whether SETD7-dependent chromatin modifications modulate angiogenic properties of human aortic endothelial cells (HAECs) cultured in growth factor-free media and exposed to normal glucose (NG) and high glucose (HG) concentrations, a well-established in vitro model mimicking diabetic ischemia. To investigate whether pharmacological blockade of SETD7 restores angiogenic properties of endothelial cells (ECs) while boosting post-ischemic vascularization of diabetic mice with hindlimb ischemia. To investigate whether our experimental findings hold true in the human setting. To this end, we investigate whether the SETD7-dependent signaling is dysregulated in muscular specimens obtained from diabetic patients with PAD. 2 Methods: Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) concentrations for 48 hours. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). In vitro assays, namely cell migration and tube formation were employed to study angiogenic properties in HAECs. SETD7 and H3K4me1 levels were investigated by Western blot and Chromatin immunoprecipitation (ChIP). Pharmacological blockade of SETD7 was achieved by using the highly selective inhibitor (R)-PFI-2. Mice with streptozotocin-induced diabetes were orally treated with (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation for 14 days. Blood flow recovery was analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Our experimental findings were also translated in gastrocnemius muscle samples from patients with and without diabetes. Results: RNA-seq in HG-treated HAECs revealed a profound upregulation of the methyltransferase SETD7, an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). SETD7 upregulation in HGtreated HAECs was associated with increased H3K4me1 levels as well as with impaired endothelial cell migration and tube formation. Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycaemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7- dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA3G). Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. In diabetic mice with hindlimb ischemia, treatment with (R)-PFI-2 improved limb vascularization and perfusion as compared to vehicle. Finally, SETD7/SEMA3G axis was upregulated in muscle specimens from T2D patients as compared to controls. Conclusion: Targeting SETD7 represents a novel epigenetic-based therapy to boost eovascularization in diabetic patients with PAD

The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies

Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the 'epigenetic landscape' in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations