Dissecting the transcriptome in cardiovascular disease.

Exercise-mediated autophagy in cardiovascular diseases.

Present throughout the vasculature, endothelial cells (ECs) are essential for blood vessel function and play a central role in the pathogenesis of diverse cardiovascular diseases. Understanding the intricate molecular determinants governing endothelial function and dysfunction is essential to develop novel clinical breakthroughs and improve knowledge. An increasing body of evidence demonstrates that long non-coding RNAs (lncRNAs) are active regulators of the endothelial transcriptome and function, providing emerging insights into core questions surrounding EC contributions to pathology, and perhaps the emergence of novel therapeutic opportunities. In this review, we discuss this class of non-coding transcripts and their role in endothelial biology during cardiovascular development, homeostasis, and disease, highlighting challenges during discovery and characterization and how these have been overcome to date. We further discuss the translational therapeutic implications and the challenges within the field, highlighting lncRNA that support endothelial phenotypes prevalent in cardiovascular disease.

Background Acute inflammation leads to increased myelopoiesis in the bone marrow and recruitment of immune cells to respective sites of injury. Yet, in certain cases of high demand such as acute tissue damage as in acute myocardial infarction (AMI), innate immune cells can be additionally recruited from lymphoid organs such as the spleen. Monocytes are important in both onset and resolution of inflammation comprising a huge repertoire of coding and non-coding RNA molecules regulating a fast-acting immune response. Long non-coding RNAs (lncRNA) emerge as novel regulatory cell-specific molecules, which are able to influence cell physiology in numerous ways. Purpose Delineate monocyte subpopulations from patients with AMI compared to healthy controls based on their non-coding transcriptome, different isoform usage and associated source of origin. Methods and results Next generation bulk RNA sequencing has been performed from human monocytes after pre-sorting for CD14 expression and subsequent separation into three major subpopulations based on their surface markers CD14 and CD16 using a FACS Aria II cell sorter. Non-coding RNA expression shows clear differences between cells from healthy controls versus patients with AMI and among subpopulations. Intensive bioinformatics analysis revealed numerous annotated lncRNA, antisense, pseudogene and circular RNAs displaying significant differences in their expression profiles. Some lncRNA show positive or negative correlations with their respective coding antisense gene or their convergent or divergent sense neighbouring gene, such as linc02207 vs MCTP2, SAP30-AS vs SAP30, BID-AS vs BID, HLX-AS vs HLX or TNFAIP3-AS vs TNFAIP3. We also identified the existence of different isoforms of certain lncRNA and a distinct preference thereof, such as linc02207- 217 isoform being most abundant. Real-time PCR was applied for validation of lncRNA expression profile and their nucleocytoplasmic distribution observing preferential nuclear expression for most lncRNA. In vitro assays for silencing and overexpression approaches as well as treatment with inflammatory stimuli and in silico bioinformatics analysis will help to unravel their functionality. Additionally mapping our bulk RNA data to deconvoluted single cell RNAseq data from publicly available human cell atlas (HCA), is applied to additionally unravel the origin of particular subpopulations within the AMI monocytes, associating their origin to either spleen or bone marrow. Conclusions High read depth bulk RNA sequencing revealed a human monocyte-specific long non-coding RNA transcriptome differentially expressed in three predefined subpopulations and disease stages. Distinct expression of lncRNA and associated coding genes as well as distinct isoform preference implies specific functionalities. Studying these molecules and their interaction partners will unravel functional participants in the development of therapeutic approaches for cardiovascular diseases. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK, SNF

Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders. To summarize the literature surrounding the eCB system in cardiovascular function and disease and the new compounds that may potentially extend the range of available interventions. Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects. Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.

Type 2 diabetic patients are known to have a tendency to develop cardiovascular (CV) disease (CVD), and related unfavourable outcomes such as heart failure, myocardial infarction (MI), cerebrovascular events (e.g. stroke), and related mortality. Long- term clinical trials have revealed contradictory findings regarding the relationship between glycemic control and CV benefits due to variations in the key characteristics of the study population. During the last decade, number of pharmacological agents used for glucose- lowering in the treatment of type 2 diabetes mellitus (T2DM) has increased owing to the introduction of dipeptidyl peptidase- IV (DPP- IV) inhibitors, glucagon- like peptide- 1 (GLP- 1) receptor agonists, and sodium-glucose co-transporter 2 (SGLT- 2) inhibitors. This review aims to focus on the mechanisms of action of these drugs in the cardiovascular system and the trials evaluating their impact on CVD. Furthermore, trials in the last decade evaluating the impact of traditional glucose- lowering drugs on CVD are included. For this purpose, we searched PubMed for articles in English using the search terms "type 2 diabetes mellitus, glucose- lowering drugs, antidiabetic medications, cardiovascular, cardiovascular disease, cardiovascular system" between inception to September 2016. We also searched separately for each medication in addition to the keyword "cardiovascular disease" on PubMed. To identify further articles, we hand searched related citations in review articles and commentaries.

Introduction

Supporting cardiac patients during the COVID-19 pandemic

The roles of androgens on cardiovascular physiology and pathophysiology are controversial as both beneficial and detrimental effects have been reported. Although the reasons for this discrepancy are unclear, multiple factors such as genetic and epigenetic variation, sex-specificity, hormone interactions, drug preparation and route of administration may contribute. Recently, growing evidence suggests that androgens exhibit beneficial effects on cardiovascular function though the mechanism remains to be elucidated. Endothelial cells (ECs) which line the interior surface of blood vessels are distributed throughout the circulatory system, and play a crucial role in cardiovascular function. Endothelial progenitor cells (EPCs) are considered an indispensable element for the reconstitution and maintenance of an intact endothelial layer. Endothelial dysfunction is regarded as an initiating step in development of atherosclerosis and cardiovascular diseases. The modulation of endothelial functions by androgens through either genomic or nongenomic signal pathways is one possible mechanism by which androgens act on the cardiovascular system. Obtaining insight into the mechanisms by which androgens affect EC and EPC functions will allow us to determine whether androgens possess beneficial effects on the cardiovascular system. This in turn may be critical in the prevention and therapy of cardiovascular diseases. This article seeks to review recent progress in androgen regulation of endothelial function, the sex-specificity of androgen actions, and its clinical applications in the cardiovascular system.

Whereas the mechanisms controlling cellular growth through protein synthesis have been investigated extensively in the cardiovascular system, especially in terms of cardiac cell hypertrophy and vascular smooth muscle cell proliferation, the processes by which endogenous proteins are degraded in these cells have received much less attention and have only begun to be revealed.The ubiquitin-proteasome system (UPS) is responsible for the degradation of 70-90% of intracellular proteins.The fundamental importance of the UPS in these degradation mechanisms was highlighted when Rose, Hershko, and Ciechanover were awarded the 2004 Nobel Prize in Chemistry for their seminal contributions in that field, i.e. the discovery of both ubiquitin 1 and the proteasome. 2 As illustrated in this Spotlight Issue, protein degradation by the UPS plays a central role in cardiovascular physiology and disease: from endothelial function, the cell cycle, and atherosclerosis to myocardial ischaemia, cardiac hypertrophy, inherited cardiomyopathies, and heart failure.Investigations on the role of the UPS in the cardiovascular system started about 15 years ago and have since increased exponentially.In the heart, the first reports demonstrated that the proteasome is responsible for the degradation of specific, stress-sensitive transcriptional regulators, such as NF-kB, HIF-1a, or inducible cAMP early repressor. 3,4It was subsequently shown that the UPS also degrades contractile proteins and components of the sarcomere. 5,6The development of several categories of proteasome-specific inhibitors further delineated a role for the UPS in multiple forms of heart disease, such as ischaemia/reperfusion, cardiac hypertrophy, cardiomyopathies, and heart failure.In the vasculature, it was initially shown that proteasome activity affects angiogenesis 7 and, subsequently, that the proteasome participates in nitric oxide metabolism, oxidative stress, and atherosclerosis.Descriptions of a dysfunction of the UPS in human heart disease also began to emerge in the literature. 8 -10 Recently, several clinical case reports have mentioned potentially cardiotoxic side effects of proteasome inhibitors, for example, in patients treated for solid tumours and haematological malignancies. 11,12l these advances have been reviewed in the current Spotlight

Cardiovascular Diseases (CVDs) as a leading cause of death worldwide inflict major stress on morbidity and societal costs. Though the studies pertaining to pathophysiology and genetics of CVDs have helped in prevention, diagnosis and treatment of diseases, there are still lacunas in our knowledge. So, novel tools that can define genomic regulation under different conditions are needed to bridge this gap. 'Epigenetic' mechanism helps the cells to quickly respond to ever changing environment by molecular mechanisms like methylation, histone modifications, nc-RNAs. These mechanisms act as a new layer of regulation in CVDs. The role of epigenetics as a key regulatory player in prevention, diagnosis and treatment of CVDs is emerging. Thus, the focus of present chapter is to decipher the role of epigenetics in CVDs and its potential to be used in risk assessment or as biomarkers in devising and deploying better diagnosis and treatment for different CVDs.

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Recognizing Pregnancy-Associated Cardiovascular Risk Factors

Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

Background and ObjectiveThe recent emergence of epitranscriptomics provides an avenue for identifying RNA modifications implicated in the pathophysiology of human disease. To date, over 170 RNA modifications have been identified; these modifications are important because they can affect the fate of RNAs, including their decay, maturation, splicing, stability, and translational efficiency. Although RNA modifications have been reported in many tissues and disease contexts, detailed functional studies in the heart and cardiovascular disease are only beginning to be reported.MethodsThe search for relevant articles related to epitranscriptomics was conducted by focusing on the cardiovascular system and disease in the PubMed database.Key Content and FindingsWe summarize the recent findings of three epitranscriptomic marks—N6-methyladenosine (m6A), adenosine to inosine (A-to-I) RNA editing, and 5-methylcytosine (m5C) as other epitranscriptomic marks are not studied extensively in the cardiovascular system and disease.ConclusionsIn this narrative review, the current status of cardiac epitranscriptomics is summarized to raise the awareness of this important field of study.

The analysis of the physiological aspects of conducting physical education classes with first graders who have cardiovascular disease is given. The research urgency is caused by the fact that recently the rate of child disability in Russia has doubled. Prevalent disabilities associated with cardiovascular diseases and their manifestations. The data analysis of morbidity and disability of children in Voronezh Region over the past five years is given, one could argue about the increase in the number of first-graders, divided in consequence to the special medical group and their reduction to the core. According to the Health Department of the Voronezh Region the highest prevalence of pathologies of the cardiovascular system in children of 7–8 years are cardiomyopathy and myocarditis various, as well as dysregulation of vascular tone, occurring in the form of neuro-circulatory dystonia. On average, pupils in the first grades of secondary institutions observed pathology of the cardiovascular system at 23.4 % of cases.We have developed a technique of physical training of correctional orientation for first graders having pathology of the cardiovascular system, including developing, gymnastic and breathing exercises that are adapted to individualisierung and dosing of the training load. The developed program allows to improve the process of physical education at physical culture lessons with first graders who have cardiovascular system disease.