Age and sex mediated effects of estrogen and Β3-adrenergic receptor on cardiovascular pathophysiology.

Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for ß-adrenergic receptors (ßARs), which are essential regulators of mammalian physiology. It has in fact been shown that ßARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences. Based on these premises, this review article focused on the ß3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how ß3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.

Noninvasive Techniques for Tracking Biological Aging of the Cardiovascular System: JACC Family Series.

Population aging is one of the most important demographic transformations of our time. Increasing the "health span"-the proportion of life spent in good health-is a global priority. Biological aging comprises molecular and cellular modifications over many years, which culminate in gradual physiological decline across multiple organ systems and predispose to age-related illnesses. Cardiovascular disease is a major cause of ill health and premature death in older people. The rate at which biological aging occurs varies across individuals of the same age and is influenced by a wide range of genetic and environmental exposures. The authors review the hallmarks of biological cardiovascular aging and their capture using imaging and other noninvasive techniques and examine how this information may be used to understand aging trajectories, with the aim of guiding individual- and population-level interventions to promote healthy aging.

The Renin-Angiotensin System and Cardiovascular-Kidney-Metabolic Syndrome: Focus on Early-Life Programming.

The identification of pathological links among metabolic disorders, kidney ailments, and cardiovascular conditions has given rise to the concept of cardiovascular-kidney-metabolic (CKM) syndrome. Emerging prenatal risk factors seem to increase the likelihood of CKM syndrome across an individual's lifespan. The renin-angiotensin system (RAS) plays a crucial role in maternal-fetal health and maintaining homeostasis in cardiovascular, metabolic, and kidney functions. This review consolidates current preclinical evidence detailing how dysregulation of the RAS during pregnancy and lactation leads to CKM characteristics in offspring, elucidating the underlying mechanisms. The multi-organ effects of RAS, influencing fetal programming and triggering CKM traits in offspring, suggest it as a promising reprogramming strategy. Additionally, we present an overview of interventions targeting the RAS to prevent CKM traits. This comprehensive review of the potential role of the RAS in the early-life programming of CKM syndrome aims to expedite the clinical translation process, ultimately enhancing outcomes in cardiovascular-kidney-metabolic health.

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture.

The interplay of various body systems, encompassing those that govern cardiovascular and metabolic functions, has evolved alongside the development of multicellular organisms. This evolutionary process is essential for the coordination and maintenance of homeostasis and overall health by facilitating the adaptation of the organism to internal and external cues. Disruption of these complex interactions contributes to the development and progression of pathologies that involve multiple organs. Obesity-associated cardiovascular risks, such as hypertension, highlight the significant influence that metabolic processes exert on the cardiovascular system. This cardiometabolic communication is reciprocal, as indicated by substantial evidence pointing to the ability of the cardiovascular system to affect metabolic processes, with pathophysiological implications in disease conditions. In this review, I outline the bidirectional nature of the cardiometabolic interaction, with special emphasis on the impact that metabolic organs have on the cardiovascular system. I also discuss the contribution of the neural circuits and autonomic nervous system in mediating the crosstalk between cardiovascular and metabolic functions in health and disease, along with the molecular mechanisms involved.

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits.

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.

Challenges in the Therapeutic Targeting of KCa Channels: From Basic Physiology to Clinical Applications.

Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

The Significance of Lipoproteins in the Development of Obesity.

Disruption of lipoprotein metabolism plays an important role in the development of several cardiovascular, inflammatory, and metabolic diseases. This review examines the importance of different types of lipoproteins and the role they play in the development of dyslipidemia in obesity. The causes and consequences associated with the disruption of lipid metabolism and its significance in the pathogenesis of obesity are considered. The relationship between such pathological processes, which occur alongside obesity as dyslipidemia and inflammation, is determined. In view of the current efficacy and toxicity limitations of currently approved drugs, natural compounds as potential therapeutic agents in the treatment of obesity are considered in the review. The complex mechanisms of lipid metabolism normalization in obesity found for these compounds can serve as one of the confirmations of their potential efficacy in treating obesity. Nanoparticles can serve as carriers for the considered drugs, which can improve their pharmacokinetic properties.

miRNAs in Heart Development and Disease.

Cardiovascular diseases (CVD) are a group of disorders that affect the heart and blood vessels. They include conditions such as myocardial infarction, coronary artery disease, heart failure, arrhythmia, and congenital heart defects. CVDs are the leading cause of death worldwide. Therefore, new medical interventions that aim to prevent, treat, or manage CVDs are of prime importance. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level and play important roles in various biological processes, including cardiac development, function, and disease. Moreover, miRNAs can also act as biomarkers and therapeutic targets. In order to identify and characterize miRNAs and their target genes, scientists take advantage of computational tools such as bioinformatic algorithms, which can also assist in analyzing miRNA expression profiles, functions, and interactions in different cardiac conditions. Indeed, the combination of miRNA research and bioinformatic algorithms has opened new avenues for understanding and treating CVDs. In this review, we summarize the current knowledge on the roles of miRNAs in cardiac development and CVDs, discuss the challenges and opportunities, and provide some examples of recent bioinformatics for miRNA research in cardiovascular biology and medicine.

Immune checkpoint inhibitors associated cardiovascular immune-related adverse events.

Immune checkpoint inhibitors (ICIs) are specialized monoclonal antibodies (mAbs) that target immune checkpoints and their ligands, counteracting cancer cell-induced T-cell suppression. Approved ICIs like cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene-3 (LAG-3) have improved cancer patient outcomes by enhancing anti-tumor responses. However, some patients are unresponsive, and others experience immune-related adverse events (irAEs), affecting organs like the lung, liver, intestine, skin and now the cardiovascular system. These cardiac irAEs include conditions like myocarditis, atherosclerosis, pericarditis, arrhythmias, and cardiomyopathy. Ongoing clinical trials investigate promising alternative co-inhibitory receptor targets, including T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT). This review delves into the mechanisms of approved ICIs (CTLA-4, PD-1, PD-L1, and LAG-3) and upcoming options like Tim-3 and TIGIT. It explores the use of ICIs in cancer treatment, supported by both preclinical and clinical data. Additionally, it examines the mechanisms behind cardiac toxic irAEs, focusing on ICI-associated myocarditis and atherosclerosis. These insights are vital as ICIs continue to revolutionize cancer therapy, offering hope to patients, while also necessitating careful monitoring and management of potential side effects, including emerging cardiac complications.

Myeloid-derived growth factor and its effects on cardiovascular and metabolic diseases.

Myeloid-derived growth factor (MYDGF) is a paracrine protein produced by bone marrow-derived monocytes and macrophages. Current research shows that it has protective effects on the cardiovascular system, such as repairing heart tissue after myocardial infarction, enhancing cardiomyocyte proliferation, improving cardiac regeneration after myocardial injury, regulating proliferation and survival of endothelial cells, reducing endothelial cell damage, resisting pressure overload-induced heart failure, as well as protecting against atherosclerosis. Furthermore, regarding the metabolic diseases, MYDGF has effects of improving type 2 diabetes mellitus, relieving non-alcoholic fatty liver disease, alleviating glomerular diseases, and resisting osteoporosis. Herein, we will discuss the biology of MYDGF and its effects on cardiovascular and metabolic diseases.

"When," "Where," and "How" of SARS-CoV-2 Infection Affects the Human Cardiovascular System: A Narrative Review.

Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of cardiovascular complications during and after acute COVID-19 infection have been hypothesized. The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of the deadliest pandemics in modern history. The myocardial injury in COVID-19 patients has been associated with coronary spasm, microthrombi formation, plaque rupture, hypoxic injury, or cytokine storm, which have the same pathophysiology as the three clinical variants of Kounis syndrome. The angiotensin-converting enzyme 2 (ACE2), reninaldosterone system (RAAS), and kinin-kallikrein system are the main proposed mechanisms contributing to cardiovascular complications with the COVID-19 infection. ACE receptors can be found in the heart, blood vessels, endothelium, lungs, intestines, testes, neurons, and other human body parts. SARS-CoV-2 directly invades the endothelial cells with ACE2 receptors and constitutes the main pathway through which the virus enters the endothelial cells. This causes angiotensin II accumulation downregulation of the ACE2 receptors, resulting in prothrombotic effects, such as hemostatic imbalance via activation of the coagulation cascade, impaired fibrinolysis, thrombin generation, vasoconstriction, endothelial and platelet activation, and pro-inflammatory cytokine release. The KKS system typically causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation, but SARS-CoV-2 infection impairs such counterbalancing effects. This cascade results in cardiac arrhythmias, cardiac arrest, cardiomyopathy, cytokine storm, heart failure, ischemic myocardial injuries, microvascular disease, Kounis syndrome, prolonged COVID, myocardial fibrosis, myocarditis, new-onset hypertension, pericarditis, postural orthostatic tachycardia syndrome, pulmonary hypertension, stroke, Takotsubo syndrome, venous thromboembolism, and thrombocytopenia. In this narrative review, we describe and elucidate when, where, and how COVID-19 affects the human cardiovascular system in various parts of the human body that are vulnerable in every patient category, including children and athletes.

[Research progress on HEG1 in cardiovascular generation and tumor development].

Heart development protein with EGF-like domains 1 (HEG1) is a novel mucin-like membrane protein with a long O-glycosylation region and EGF domain. HEG1 plays critical roles in embryo development and cardiogenesis, and is closely related to the occurrence and progression of malignant tumors. Here this article demonstrates the research progress on HEG1 in cardiovascular formation and tumor development in recent years, to inspire new ideas for the pathogenesis, diagnosis and treatment of related diseases.

Insight into modulators of sphingosine-1-phosphate receptor and implications for cardiovascular therapeutics.

Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses.

AIM: To place the consequences of calcineurin inhibition in a cardiovascular context. METHODS: Literature review coupled with personal encounters. RESULTS: Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. CONCLUSION: Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

Inhibiting Monoamine Oxidase in CNS and CVS would be a Promising Approach to Mitigating Cardiovascular Complications in Neurodegenerative Disorders.

The flavoenzyme monoamine oxidases (MAOs) are present in the mitochondrial outer membrane and are responsible for the metabolism of biogenic amines. MAO deamination of biological amines produces toxic byproducts such as amines, aldehydes, and hydrogen peroxide, which are significant in the pathophysiology of multiple neurodegenerative illnesses. In the cardiovascular system (CVS), these by-products target the mitochondria of cardiac cells leading to their dysfunction and producing redox imbalance in the endothelium of the blood vessels. This brings up the biological relationship between the susceptibility of getting cardiovascular disorders in neural patients. In the current scenario, MAO inhibitors are highly recommended by physicians worldwide for the therapy and management of various neurodegenerative disorders. Many interventional studies reveal the benefit of MAO inhibitors in CVS. Drug candidates who can target both the central and peripheral MAO could be a better to compensate for the cardiovascular comorbidities observed in neurodegenerative patients.

Inflammation Resolution in the Cardiovascular System: Arterial Hypertension, Atherosclerosis, and Ischemic Heart Disease.

Significance: Chronic inflammation has emerged as a major underlying cause of many prevalent conditions in the Western world, including cardiovascular diseases. Although targeting inflammation has emerged as a promising avenue by which to treat cardiovascular disease, it is also associated with increased risk of infection. Recent Advances: Though previously assumed to be passive, resolution has now been identified as an active process, mediated by unique immunoresolving mediators and mechanisms designed to terminate acute inflammation and promote tissue repair. Recent work has determined that failures of resolution contribute to chronic inflammation and the progression of human disease. Specifically, failure to produce pro-resolving mediators and the impaired clearance of dead cells from inflamed tissue have been identified as major mechanisms by which resolution fails in disease. Critical Issues: Drawing from a rapidly expanding body of experimental and clinical studies, we review here what is known about the role of inflammation resolution in arterial hypertension, atherosclerosis, myocardial infarction, and ischemic heart disease. For each, we discuss the involvement of specialized pro-resolving mediators and pro-reparative cell types, including T regulatory cells, myeloid-derived suppressor cells, and macrophages. Future Directions: Pro-resolving therapies offer the promise of limiting chronic inflammation without impairing host defense. Therefore, it is imperative to better understand the mechanisms underlying resolution to identify therapeutic targets. Antioxid. Redox Signal. 40, 292-316.

Regulatory effects of curcumin on nitric oxide signaling in the cardiovascular system.

The continuously rising prevalence of cardiovascular disease (CVD) globally substantially impacts the economic growth of developing countries. Indeed, one of the leading causes of death worldwide is unfavorable cardiovascular events. Reduced nitric oxide (NO) generation is the pathogenic foundation of endothelial dysfunction, which is regarded as the first stage in the development of a number of CVDs. Nitric oxide exerts an array of biological effects, including vasodilation, the suppression of vascular smooth muscle cell proliferation and the functional control of cardiac cells. Numerous treatment strategies aim to increase NO synthesis or upregulate downstream NO signaling pathways. The major component of Curcuma longa, curcumin, has long been utilized in traditional medicine to treat various illnesses, especially CVDs. Curcumin improves CV function as well as having important pleiotropic effects, such as anti-inflammatory and antioxidant, through its ability to increase the bioavailability of NO and to positively impact NO-related signaling pathways. In this review, we discuss the scientific literature relating to curcumin's positive effects on NO signaling and vascular endothelial function.

Potential Role of GLP-1 Based Therapeutics in Coronary Artery Disease.

Glucagon-like peptide-1 (GLP-1), an incretin hormone primarily secreted by intestinal L cells, regulates glucose metabolism by increasing insulin synthesis and secretion, decreasing plasma glucagon levels, reducing food intake, and slowing gastric emptying. This has led to the development of GLP-1 receptor (GLP-1R) agonists as a treatment for diabetes and obesity. In addition to being present in beta cells, GLP-1R has also been identified in blood vessels and the heart, suggesting that GLP-1R agonists may have an impact on cardiovascular health. There is now substantial evidence supporting GLP-1's protective effects on the cardiovascular system. This review summarizes the current research on GLP-1-based therapy for coronary artery disease (CAD) by examining its protective effects against inflammation and ischemia/reperfusion injury and analyzing clinical trials on GLP-1-based therapies for CAD. Although results from various studies were inconsistent, the challenge of transitioning GLP-1-based therapies from the laboratory to the clinical setting remains. Further well-designed and high-quality studies are necessary to determine the efficacy and safety of GLP-1 for patients with CAD.

Interaction between Selected Adipokines and Musculoskeletal and Cardiovascular Systems: A Review of Current Knowledge.

Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in the human body are also looked at. The role of adipokine seems crucial in developing future therapies for pathologies of selected systems. In this study, we look at selected adipokines, leptin, adiponectin, chemerin, resistin, omentin-1, nesfatin, irisin-1, visfatin, apelin, vaspin, heparin-binding EGF-like growth factor (HB-EGF), and TGF-ß2, and how they affect systems in the human body related to physical activity such as the musculoskeletal and cardiovascular systems.

Blood-Derived Lipid and Metabolite Biomarkers in Cardiovascular Research from Clinical Studies: A Recent Update.

The primary prevention, early detection, and treatment of cardiovascular disease (CVD) have been long-standing scientific research goals worldwide. In the past decades, traditional blood lipid profiles have been routinely used in clinical practice to estimate the risk of CVDs such as atherosclerotic cardiovascular disease (ASCVD) and as treatment targets for the primary prevention of adverse cardiac events. These blood lipid panel tests often fail to fully predict all CVD risks and thus need to be improved. A comprehensive analysis of molecular species of lipids and metabolites (defined as lipidomics and metabolomics, respectively) can provide molecular insights into the pathophysiology of the disease and could serve as diagnostic and prognostic indicators of disease. Mass spectrometry (MS) and nuclear magnetic resonance (NMR)-based lipidomics and metabolomics analysis have been increasingly used to study the metabolic changes that occur during CVD pathogenesis. In this review, we provide an overview of various MS-based platforms and approaches that are commonly used in lipidomics and metabolomics workflows. This review summarizes the lipids and metabolites in human plasma/serum that have recently (from 2018 to December 2022) been identified as promising CVD biomarkers. In addition, this review describes the potential pathophysiological mechanisms associated with candidate CVD biomarkers. Future studies focused on these potential biomarkers and pathways will provide mechanistic clues of CVD pathogenesis and thus help with the risk assessment, diagnosis, and treatment of CVD.