Adenosine and its receptors in the heart: regulation, retaliation and adaptation

The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A(1), A(2A), A(2B), and A(3)ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity (e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.     

A system-level investigation into the mechanisms of chinese traditional medicine: compound danshen formula for cardiovascular disease treatment

Compound Danshen Formula (CDF) is a widely used Traditional Chinese Medicine (TCM) which has been extensively applied in clinical treatment of cardiovascular diseases (CVDs). However, the underlying mechanism of clinical administrating CDF on CVDs is not clear. In this study, the pharmacological effect of CDF on CVDs was analyzed at a systemic point of view. A systems-pharmacological model based on chemical, chemogenomics and pharmacological data is developed via network reconstruction approach. By using this model, we performed a high-throughput in silico screen and obtained a group of compounds from CDF which possess desirable pharmacodynamical and pharmacological characteristics. These compounds and the corresponding protein targets are further used to search against biological databases, such as the compound-target associations, compound-pathway connections and disease-target interactions for reconstructing the biologically meaningful networks for a TCM formula. This study not only made a contribution to a better understanding of the mechanisms of CDF, but also proposed a strategy to develop novel TCM candidates at a network pharmacology level.     

CardioGenBase: A Literature Based Multi-Omics Database for Major Cardiovascular Diseases

Cardiovascular diseases (CVDs) account for high morbidity and mortality worldwide. Both, genetic and epigenetic factors are involved in the enumeration of various cardiovascular diseases. In recent years, a vast amount of multi-omics data are accumulated in the field of cardiovascular research, yet the understanding of key mechanistic aspects of CVDs remain uncovered. Hence, a comprehensive online resource tool is required to comprehend previous research findings and to draw novel methodology for understanding disease pathophysiology. Here, we have developed a literature-based database, CardioGenBase, collecting gene-disease association from Pubmed and MEDLINE. The database covers major cardiovascular diseases such as cerebrovascular disease, coronary artery disease (CAD), hypertensive heart disease, inflammatory heart disease, ischemic heart disease and rheumatic heart disease. It contains ~1,500 cardiovascular disease genes from ~2,4000 research articles. For each gene, literature evidence, ontology, pathways, single nucleotide polymorphism, protein-protein interaction network, normal gene expression, protein expressions in various body fluids and tissues are provided. In addition, tools like gene-disease association finder and gene expression finder are made available for the users with figures, tables, maps and venn diagram to fit their needs. To our knowledge, CardioGenBase is the only database to provide gene-disease association for above mentioned major cardiovascular diseases in a single portal. CardioGenBase is a vital online resource to support genome-wide analysis, genetic, epigenetic and pharmacological studies.     

The role of SARS-CoV-2 target ACE2 in cardiovascular diseases

SARS-CoV-2, the virus responsible for the global coronavirus disease (COVID-19) pandemic, attacks multiple organs of the human body by binding to angiotensin-converting enzyme 2 (ACE2) to enter cells. More than 20 million people have already been infected by the virus. ACE2 is not only a functional receptor of COVID-19 but also an important endogenous antagonist of the renin-angiotensin system (RAS). A large number of studies have shown that ACE2 can reverse myocardial injury in various cardiovascular diseases (CVDs) as well as is exert anti-inflammatory, antioxidant, anti-apoptotic and anticardiomyocyte fibrosis effects by regulating transforming growth factor beta, mitogen-activated protein kinases, calcium ions in cells and other major pathways. The ACE2/angiotensin-(1-7)/Mas receptor axis plays a decisive role in the cardiovascular system to combat the negative effects of the ACE/angiotensin II/angiotensin II type 1 receptor axis. However, the underlying mechanism of ACE2 in cardiac protection remains unclear. Some approaches for enhancing ACE2 expression in CVDs have been suggested, which may provide targets for the development of novel clinical therapies. In this review, we aimed to identify and summarize the role of ACE2 in CVDs.     

Role of non-coding variants in cardiovascular disease

Cardiovascular diseases (CVDs) constitute one of the significant causes of death worldwide. Different pathological states are linked to CVDs, which despite interventions and treatments, still have poor prognoses. The genetic component, as a beneficial tool in the risk stratification of CVD development, plays a role in the pathogenesis of this group of diseases. The emergence of genome-wide association studies (GWAS) have led to the identification of non-coding parts associated with cardiovascular traits and disorders. Variants located in functional non-coding regions, including promoters/enhancers, introns, miRNAs and 5′/3′ UTRs, account for 90% of all identified single-nucleotide polymorphisms associated with CVDs. Here, for the first time, we conducted a comprehensive review on the reported non-coding variants for different CVDs, including hypercholesterolemia, cardiomyopathies, congenital heart diseases, thoracic aortic aneurysms/dissections and coronary artery diseases. Additionally, we present the most commonly reported genes involved in each CVD. In total, 1469 non-coding variants constitute most reports on familial hypercholesterolemia, hypertrophic cardiomyopathy and dilated cardiomyopathy. The application and identification of non-coding variants are beneficial for the genetic diagnosis and better therapeutic management of CVDs.     

Exosomes in Mesenchymal Stem Cells,a New Therapeutic Strategy for Cardiovascular Diseases?

Cardiovascular diseases (CVDs) are still a major cause of people deaths worldwide, and mesenchymal stem cells (MSCs) transplantation holds great promise due to its capacity to differentiate into cardiovascular cells and secrete protective cytokines, which presents an important mechanism of MSCs therapy for CVDs. Although the capability of MSCs to differentiate into cardiomyocytes (CMCs), endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) has been well recognized in massive previous experiments both in vitro and in vivo, low survival rate of transplanted MSCs in recipient hearts suggests that therapeutic effects of MSCs transplantation might be also correlated with other underlying mechanisms. Notably, recent studies uncovered that MSCs were able to secret cholesterol-rich, phospholipid exosomes which were enriched with microRNAs (miRNAs). The released exosomes from MSCs acted on hearts and vessels, and then exerted anti-apoptosis, cardiac regeneration, anti-cardiac remodeling, anti-inflammatory effects, neovascularization and anti-vascular remodeling, which are considered as novel molecular mechanisms of therapeutic potential of MSCs transplantation. Here we summarized recent advances about the role of exosomes in MSCs therapy for CVDs, and discussed exosomes as a novel approach in the treatment of CVDs in the future.     

Insights into circular RNAs: Biogenesis,function and their regulatory roles in cardiovascular disease

As a distinctive member of the noncoding RNA family, circular RNAs (circRNAs) are generated from single-stranded, covalently closed structures and are ubiquitous in mammalian cells and tissues. Due to its atypical circular architecture, it was conventionally deemed insignificant dark matter for a prolonged duration. Nevertheless, studies conducted over the last decade have demonstrated that this abundant, structurally stable and tissue-specific RNA has been increasingly relevant in diverse diseases, including cancer, neurological disorders, diabetes mellitus and cardiovascular diseases (CVDs). Therefore, regulatory pathways controlled by circRNAs are widely involved in the occurrence and pathological processes of CVDs through their function as miRNA sponges, protein sponges and protein scaffolds. To better understand the role of circRNAs and their complex regulatory networks in CVDs, we summarize current knowledge of their biogenesis and function and the latest research on circRNAs in CVDs, with the hope of paving the way for the identification of promising biomarkers and therapeutic strategies for CVDs.     

腺苷及其衍生物的心血管效应和作用机制

在实验中观察了腺苷及其衍生物的心血管效应和作用机制,结果表明：（１）腺苷和２－氯腺苷先引起由颈动脉体化学感受器内的Ａ２受体所中介的血压短暂升高,随之为心血管系统Ａ１和Ａ２受体中介的持久而明显的血压降低;（２）腺苷受体激动剂环戊腺苷抑制窦房结起搏细胞的电生理活动;（３）环戊腺苷减弱异丙肾上腺素诱发的早发和迟发性后除极及触发电活动;（４）内源性腺苷参与无氧所致的心率减慢;（５）预缺血时腺苷受体的激活及     

Circular RNA in cardiovascular disease: Expression,mechanisms and clinical prospects

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non-coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.     

Strategies and challenges for non-viral delivery of non-coding RNAs to the heart

Non‐coding RNAs (ncRNAs), such as miRNAs and long non‐coding RNAs (lncRNAs) have been reported as regulators of cardiovascular pathophysiology. Their transient effect and diversified mechanisms of action offer a plethora of therapeutic opportunities for cardiovascular diseases (CVDs). However, physicochemical RNA features such as charge, stability, and structural organization hinder efficient on-target cellular delivery. Here, we highlight recent preclinical advances in ncRNA delivery for the cardiovascular system using non‐viral approaches. We identify the unmet needs and advance possible solutions towards clinical translation. Finding the optimal delivery vehicle and administration route is vital to improve therapeutic efficacy and safety; however, given the different types of ncRNAs, this may ultimately not be frameable within a one-size-fits-all approach.     

Cadmium and cardiovascular diseases: cell biology,pathophysiology, and epidemiological relevance

Today cardiovascular diseases (CVDs) are the killer number one world wide. In 2004 an estimated 17.1 million people died due to CVDs and this number will further increase to an estimated 23.6 million by 2030. Importantly, currently known risk factors, like hypertension, and hypercholesterolemia, can only be made responsible for about 50–75% of all CVDs, highlighting the urgent need to search for and define new CVD risk factors. Cadmium (Cd) was shown to have the potential to serve as one such novel risk factor, as it was demonstrated—in vitro, in animal studies, and in human studies—that Cd causes atherosclerosis (the basis of most CVDs). Herein, we discuss the molecular and cellular biological effects of Cd in the cardiovascular system; we present concepts on the pathophysiology of Cd-caused atherosclerosis, and provide data that indicate an epidemiological relevance of Cd as a risk factor for CVDs.     

Small but significant: Insights and new perspectives of exosomes in cardiovascular disease

Cardiovascular diseases (CVDs) are a major health problem worldwide, and health professionals are still actively seeking new and effective approaches for CVDs treatment. Presently, extracellular vesicles, particularly exosomes, have gained its popularity for CVDs treatment because of their function as messengers for inter‐ and extra‐cellular communications to promote cellular functions in cardiovascular system. However, as a newly developed field, researchers are still trying to fully understand the role of exosomes, and their mechanism in mediating cardiac repair process. Therefore, a comprehensive review of this topic can be timely and favourable. In this review, we summarized the basic biogenesis and characterization of exosomes and then further extended the focus on the circulating exosomes in cellular communication and stem cell‐derived exosomes in cardiac disease treatment. In addition, we covered interactions between the heart and other organs through exosomes, leading to the diagnostic characteristics of exosomes in CVDs. Future perspectives and limitations of exosomes in CVDs were also discussed with a special focus on exploring the potential delivery routes, targeting the injured tissue and engineering novel exosomes, as well as its potential as one novel target in the metabolism‐related puzzle.     

Quantitative proteomics reveals PPAR signaling pathway regulates the cardiomyocyte activity of neonatal mouse heart

Cardiovascular diseases (CVDs) are among the most morbid and deadly types of diseases worldwide, while the existing therapeutic approaches all have their limitations. Mouse heart undergoes a very complex postnatal developmental process, including the 1-week window in which cardiomyocytes (CMs) maintain relatively high cell activity. The underlying mechanism provides an attractive direction for CVDs treatment. Herein, we collected ventricular tissues from mice of different ages from E18.5D to P8W and performed iTRAQ-based quantitative proteomics to characterize the atlas of cardiac development. A total of 3422 proteins were quantified at all selected time points, revealing critical proteomic changes related to cardiac developmental events such as the metabolic transition from glycolysis to beta-oxidation. A cluster of significantly dysregulated proteins containing proteins that have already been reported to be associated with cardiac regeneration (Erbb2, Agrin, and Hmgb) was identified. Meanwhile, the peroxisome proliferator-activated receptor (PPAR) signaling pathway (Cpt1α, Hmgcs2, Plin2, and Fabp4) was also found specifically enriched. We further revealed that bezafibrate, a pan-activator of PPAR signaling pathway markedly enhanced H9C2 cardiomyocyte activity via enhancing Cpt1α expression. This work provides new hint that activation of PPAR signaling pathway could potentially be a therapeutic strategy for the treatment of CVDs.     

Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment,current status,and perspectives

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.     

MicroRNAs在心血管自噬中的调节作用

自噬作为一种进化上高度保守的细胞降解途径,其调节异常与心血管疾病的发生、发展密切相关.研究显示,在心血管系统中,基础水平自噬对维持心肌正常收缩和传导至关重要,而在缺血/再灌注损伤和心力衰竭等心血管病理状态下,自噬水平明显增强.细胞自噬是一种多基因参与的复杂过程,近年来越来越多的证据表明,microRNAs(miRNAs)在心血管系统发育、正常生理功能维持以及不同心血管疾病(cardiovascular disease,CVDs)自噬中具有重要调节作用.本文通过对miRNAs与CVDs自噬调节方面的进展进行归纳,针对miRNAs对CVDs自噬的潜在机制进行总结,望为心血管疾病的诊断和治疗提供新的方向.     

The role of intestinal microbiota in cardiovascular disease

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.     

Emerging role of interleukin-13 in cardiovascular diseases: A ray of hope

Despite the great progress made in the treatment for cardiovascular diseases (CVDs), the morbidity and mortality of CVDs remains high due to the lack of effective treatment strategy. Inflammation is a central pathophysiological feature of the heart in response to both acute and chronic injury, while the molecular basis and underlying mechanisms remains obscure. Interleukin (IL)-13, a pro-inflammatory cytokine, has been known as a critical mediator in allergy and asthma. Recent studies appraise the role of IL-13 in CVDs, revealing that IL-13 is not only involved in more obvious cardiac inflammatory diseases such as myocarditis but also relevant to acute or chronic CVDs of other origins, such as myocardial infarction and heart failure. The goal of this review is to summarize the advancement in our knowledge of the regulations and functions of IL-13 in CVDs and to discuss the possible mechanisms of IL-13 involved in CVDs. We highlight that IL-13 may be a promising target for immunotherapy in CVDs.     

Animal models for the study of adenosine receptor function

Adenosine receptors represent a family of G-protein coupled receptors that are ubiquitously expressed in a wide variety of tissues. This family contains four receptor subtypes: A1 and A3, which mediate inhibition of adenylyl cyclase; and A2a and A2b, which mediate stimulation of this enzyme. Currently, all receptor subtypes have been genetically deleted in mouse models except for the A2b adenosine receptor, and some have been overexpressed in selective tissues of transgenic mice. Studies involving these transgenic mice indicated that receptor levels are rate limiting, as effects were amplified upon increases in receptor level. The knockout models pointed to clusters of activities related to the physiologies of the cardiovascular and the nervous systems, which are either reduced or enhanced upon specific receptor deletion. Interestingly, the trend of effects on these systems is similar in the A1 and A3 adenosine receptor knockout mice and opposite to the effects observed in the A2a adenosine receptor knockout model. This review summarizes in vitro studies on pathways affected by each adenosine receptor, and primarily focuses on the above in vivo models generated to investigate the physiologic role of adenosine receptors. Furthermore, it illustrates the need for multiple adenosine receptor subtype deficiency studies in mice and the deletion of the A2b subtype.     

PD 116,948, a highly selective A1 adenosine receptor antagonist

(R)-N-(1-Methyl-2-phenylethyl) adenosine (R-PIA), an adenosine receptor agonist has both negative chronotropic activity and coronary vasodilator activity. These actions of R-PIA are proposed to be mediated by subtypes (A1 and A2) of adenosine receptors. PD 116,948 is a xanthine derivative which is a highly selective A1 adenosine receptor ligand. In this study PD 116,948 selectively antagonized the negative chronotropic activity of R-PIA in the isolated rat heart. These results are consistent with, and add further support to the hypothesis that adenosine receptor agonists mediate their negative chronotropic activity via A1 receptors and their vasodilator activity via A2 receptors.