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

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

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

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

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

The epigenetic landscape in the cardiovascular complications of diabetes

A growing body of evidence suggests that epigenetic modifications-changes to the genome that do not involve changes in DNA sequence-may significantly derail transcriptional programs implicated in angiogenesis, oxidative stress and inflammation, thus fostering cardiovascular damage in patients with diabetes. Notably, adverse epigenetic signals acquired over the life course can be transmitted to the offspring, and may contribute to early cardiovascular phenotypes in the young generations. Hyperglycaemia and insulin resistance-key hallmarks of diabetes-induce an array of epigenetic modifications (i.e., DNA methylation, histone marks, and non-coding RNAs) which are responsible for a long-lasting impairment of vascular and cardiac function, even after intensive glycemic control. Hence, unveiling the "epigenetic landscape" in patients with diabetes may provide a post-genomic snapshot of global cardiovascular risk, and may furnish the tools to design personalized, epigenetic-based therapies to alleviate the burden of cardiovascular disease in diabetic patients. The present review aims to acquaint the scientific community with the rapidly advancing field of epigenetics and its implications in the cardiovascular complications of diabetes

Epigenetic Control of Mitochondrial Function in the Vasculature

The molecular signatures of epigenetic regulation and chromatin architecture are emerging as pivotal regulators of mitochondrial function. Recent studies unveiled a complex intersection among environmental factors, epigenetic signals, and mitochondrial metabolism, ultimately leading to alterations of vascular phenotype and increased cardiovascular risk. Changing environmental conditions over the lifetime induce covalent and post-translational chemical modification of the chromatin template which sensitize the genome to establish new transcriptional programs and, hence, diverse functional states. On the other hand, metabolic alterations occurring in mitochondria affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and gene transcription. Indeed, several components of the epigenetic machinery require intermediates of cellular metabolism (ATP, AcCoA, NADH, α-ketoglutarate) for enzymatic function. In the present review, we describe the emerging role of epigenetic modifications as fine tuners of gene transcription in mitochondrial dysfunction and vascular disease. Specifically, the following aspects are described in detail: (i) mitochondria and vascular function, (ii) mitochondrial ROS, (iii) epigenetic regulation of mitochondrial function; (iv) the role of mitochondrial metabolites as key effectors for chromatin-modifying enzymes; (v) epigenetic therapies. Understanding epigenetic routes may pave the way for new approaches to develop personalized therapies to prevent mitochondrial insufficiency and its complications

Adeno-Associated Virus-Mediated Gain-of-Function mPCSK9 Expression in the Mouse Induces Hypercholesterolemia, Monocytosis, Neutrophilia, and a Hypercoagulative State

Hypercholesterolemia has previously been induced in the mouse by a single intravenous injection of adeno-associated virus (AAV)-based vector harboring gain-of-function pro-protein convertase subtilisin/kexin type 9. Despite the recent emergence of the PCSK9-AAV model, the profile of hematological and coagulation parameters associated with it has yet to be characterized. We injected 1.0 × 1011 viral particles of mPCSK9-AAV or control AAV into juvenile male C57BL/6N mice and fed them with either a Western-type high-fat diet (HFD) or standard diet over the course of 3 weeks. mPCSK9-AAV mice on HFD exhibited greater plasma PCSK9 concentration and lower low-density lipoprotein levels, concomitant with increased total cholesterol and non-high-density lipoprotein (non-HDL)-cholesterol concentrations, and lower HDL-cholesterol concentrations than control mice. Furthermore, mPCSK9-AAV-injected mice on HFD exhibited no signs of atherosclerosis at 3 weeks after the AAV injection. Hypercholesterolemia was associated with a thromboinflammatory phenotype, as neutrophil levels, monocyte levels, and neutrophil-to-lymphocyte ratios were higher and activated partial thromboplastin times (aPTTs) was lower in HFD-fed mPCSK9-AAV mice. Therefore, the mPCSK9-AAV is a suitable model of hypercholesterolemia to examine the role of thromboinflammatory processes in the pathogenesis of cardiovascular and cerebrovascular diseases

Epigenetic processing in cardiometabolic disease

Albeit a consistent body of evidence supports the notion that genes influence cardiometabolic features and outcomes, the "non-genetic regulation" of this process is gaining increasing attention. Plastic chemical changes of DNA/histone complexes - known as epigenetic changes - critically determine gene activity by rapidly modifying chromatin accessibility to transcription factors. In this review, we describe the emerging role of chromatin modifications as fine tuners of gene transcription in adipogenesis, insulin resistance, macrophage polarization, immuno-metabolism, endothelial dysfunction and metabolic cardiomyopathy. Epigenetic processing participates in the dynamic interplay among different organs in the cardiometabolic patient. DNA methylation and post-translational histone modifications in both visceral and subcutaneous adipose tissue enable the transcription of genes implicated in lipo- and adipogenesis, inflammation and insulin resistance. Along the same line, complex networks of chromatin modifying enzymes are responsible for impaired nitric oxide bioavailability and defective insulin signalling in the vasculature, thus leading to reduced capillary recruitment and insulin delivery in the liver, skeletal muscle and adipose tissue. Furthermore, changes in methylation status of IL-4, IFNγ and Forkhead box P3 (Foxp3) gene loci are crucial for the polarization of immune cells, thus leading to adipose tissue inflammation and atherosclerosis. Cell-specific epigenetic information could advance our understanding of cardiometabolic processes, thus leading to individualized risk assessment and personalized therapeutic approaches in patients with cardiometabolic disturbances. The development of new chromatin modifying drugs indicates that targeting epigenetic changes is a promising approach to reduce the burden of cardiovascular disease in this setting