ACE2: A novel therapeutic target for cardiovascular diseases

Hypertension afflicts over 65 million Americans and poses an increased risk for cardiovascular morbidity such as stroke, myocardial infarction and end-stage renal disease resulting in significant mortality. Overactivity of the renin-angiotensin system (RAS) has been identified as an important determinant that is implicated in the etiology of these diseases and therefore represents a major target for therapy. In spite of the successes of drugs inhibiting various elements of the RAS, the incidence of hypertension and cardiovascular diseases remain steadily on the rise. This has lead many investigators to seek novel and innovative approaches, taking advantage of new pathways and technologies, for the control and possibly the cure of hypertension and related pathologies. The main objective of this review is to forward the concept that gene therapy and the genetic targeting of the RAS is the future avenue for the successful control and treatment of hypertension and cardiovascular diseases. We will present argument that genetic targeting of angiotensin-converting enzyme 2 (ACE2), a newly discovered member of the RAS, is ideally poised for this purpose. This will be accomplished by discussion of the following: (i) summary of our current understanding of the RAS with a focus on the systemic versus tissue counterparts as they relate to hypertension and other cardiovascular pathologies; (ii) the newly discovered ACE2 enzyme with its physiological and pathophysiological implications; (iii) summary of the current antihypertensive pharmacotherapy and its limitations; (iv) the discovery and design of ACE inhibitors; (v) the emerging concepts for ACE2 drug design; (vi) the current status of genetic targeting of the RAS; (vii) the potential of ACE2 as a therapeutic target for hypertension and cardiovascular disease treatment; and (viii) future perspectives for the treatment of cardiovascular diseases.     

血管紧张素转换酶2-血管紧张素1-7-Mas轴对血管作用的研究进展

血管紧张素转换酶2（ACE2）和Mas受体的发现使人们对肾素-血管紧张素（RAS）有了更全面的认识。ACE2可水解血管紧张素Ⅰ和血管紧张素Ⅱ直接或间接生成血管紧张素1-7（Ang 1-7）,并与高血压的形成密切相关。Ang 1-7主要通过Mas受体引起血管舒张、抑制细胞增殖。ACE2-Ang1-7-Mas轴的发现为RAS的研究、高血压等心血管疾病的防治和新药开发提供了新的思路和方向。     

Role of brain renin angiotensin system in neurodegeneration: An update

Renin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1–7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1–7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain.     

Intracardiac intracellular angiotensin system in diabetes

The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.     

Angiotensin III: A physiological relevant peptide of the renin angiotensin system

The renin angiotensin system (RAS) is a peptide hormone system that plays an important role in the pathophysiology of various diseases, including congestive heart failure, hypertension, myocardial infarction, and diabetic nephropathy. This has led researchers to focus extensively on this system, leading to the discovery of various peptides, peptidases, receptors and signal transduction mechanisms intrinsic to the RAS. Angiotensinogen (AGT), angiotensin (Ang) II, Ang III, Ang IV, and Ang-(1–7) are the main biologically active peptides of RAS. However, most of the available studies have focused on Ang II as the likely key peptide from the RAS that directly and indirectly regulates physiological functions leading to pathological conditions. However, data from recent studies suggest that Ang III may produce physiologically relevant effects that are similar to those produced by Ang II. Hence, this review focuses on Ang III and the myriad of physiological effects that it produces in the body.     

Physiological genomic analysis of the brain renin-angiotensin system

The brain renin-angiotensin system (RAS) has long been considered pivotal in cardiovascular regulation and important in the pathogenesis of hypertension and heart failure. However, despite more than 30 years of study, the brain RAS continues to defy explanation. Our lack of understanding of how the brain RAS is organized at the cellular and regional levels has made it difficult to resolve long-sought questions of how ANG II is produced in the brain and the precise mechanisms by which it exerts its actions. A major reason for this is the difficulty in experimentally dissecting the brain RAS at the regional, cellular, and whole organism levels. Recently, we and others developed a series of molecular tools for selective manipulation of the murine brain RAS, in parallel with technologies for integrative analysis of cardiovascular and volume homeostasis in the conscious mouse. This review, based in part on a lecture given in conjunction with the American Physiological Society Young Investigator Award in Regulatory and Integrative Physiology (Water and Electrolyte Homeostasis Section), outlines the physiological genomics strategy that we have taken in an effort to unravel some of the complexities of this system. It also summarizes the principles, progress, and prospects for a better understanding of the brain RAS in health and disease.     

What have we learned about the kallikrein-kinin and renin-angiotensin systems in neurological disorders?

The kallikrein-kinin system(KKS) is an intricate endogenous pathway involved in several physiological and pathological cascades in the brain. Due to the pathological effects of kinins in blood vessels and tissues, their formation and degradation are tightly controlled. Their components have been related to several central nervous system diseases such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy and others. Bradykinin and its receptors(B1R and B2R) may have a role in the pathophysiology of certain central nervous system diseases. It has been suggested that kinin B1R is up-regulated in pathological conditions and has a neurodegenerative pattern, while kinin B2R is constitutive and can act as a neuroprotective factor in many neurological conditions. The renin angiotensin system(RAS) is an important blood pressure regulator and controls both sodium and water intake. AngⅡ is a potent vasoconstrictor molecule and angiotensin converting enzyme is the major enzyme responsible for its release. AngⅡ acts mainly on the AT1 receptor, with involvement in several systemic and neurological disorders. Brain RAS has been associated with physiological pathways, but is also associated with brain disorders. This review describes topics relating to the involvement of both systems in several forms of brain dysfunction and indicates components of the KKS and RAS that have been used as targets in several pharmacological approaches.     

Modeling human diseases in Caenorhabditis elegans

Genes linked to human diseases often function in evolutionarily conserved pathways, which can be readily dissected in simple model organisms. Because of its short lifespan and well-known biology, coupled with a completely sequenced genome that shares extensive homology with that of mammals, Caenorhabditis elegans is one of the most versatile and powerful model organisms. Research in C. elegans has been instrumental for the elucidation of molecular pathways implicated in many human diseases. In this review, we introduce C. elegans as a model organism for biomedical research and we survey recent relevant findings that shed light on the basic molecular determinants of human disease pathophysiology. The nematode holds promise of providing clear leads towards the identification of potential targets for the development of new therapeutic interventions against human diseases.     

Proteomic Approaches to Decipher Mechanisms Underlying Pathogenesis in Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). The cause of MS is unknown, with no effective therapies available to halt the progressive neurological disability. Development of new and improvement of existing therapeutic strategies therefore require a better understanding of MS pathogenesis, especially during the progressive phase of the disease. This can be achieved through development of biomarkers that can help to identify disease pathophysiology and monitor disease progression. Proteomics is a powerful and promising tool to accelerate biomarker detection and contribute to novel therapeutics. In this review, an overview of how proteomic technology using CNS tissues and biofluids from MS patients has provided important clues to the pathogenesis of MS is provided. Current publications, pitfalls, as well as directions of future research involving proteomic approaches to understand the pathogenesis of MS are discussed.     

Beta-adrenergic axis and heart disease

Beta-adrenergic receptors (beta-ARs) belong to a large family of G-protein-coupled receptors (GPCRs) that form the interface between the sympathetic nervous system and the cardiovascular system. The beta-AR signal system is one of the most powerful regulators of cardiac function, mediated by the effects of the sympathetic transmitters epinephrine and norepinephrine. In a number of cardiac diseases, however, the biology of beta-AR signaling pathways is altered dramatically. Here we discuss the role of beta-AR signaling in the normal and abnormal heart and how the use of genetically engineered mouse models has helped in our understanding of the pathophysiology of cardiac disease.     

An update on the islet renin-angiotensin system

The traditional renin-angiotensin system (RAS) components have been studied extensively since the rate-limiting component of RAS, renin, was first characterized. The ongoing identification of various novel RAS components and signaling pathways continues to elaborate the complexity of this system. Regulation of RAS according to the conventional and contemporary views of its functions in various tissues under pathophysiological conditions is a main treatment strategy for many metabolic diseases. The local pancreatic RAS, first proposed to exist in pancreatic islets two decades ago, could regulate islet function and glycemic control via influences on islet cell mass, inflammation, and ion channels. Insulin secretion, the major function of pancreatic islets, is controlled by numerous factors. Among these factors and of particular interest are glucagon-like peptide-1 (GLP-1) and vitamin D, which may regulate islet function by directly binding receptors on islet beta cells. These factors may work with local RAS signaling in islets to protect and maintain islet function under diabetic and hyperglycemic conditions. In this concise review, the local islet RAS will be discussed with particular attention being paid to recent notable findings.     

Polymorphisms of pro-inflammatory genes and prostate cancer risk: a pharmacogenomic approach

In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors’ laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical manifestation of the malady, where treatment might play a decisive role in preventing or significantly retarding the manifestation of the disease. The better understanding of the function and the regulation of inflammatory pathway in PCa may help to know the mechanisms of its formation and progression, as well as to identify new targets for the refinement of new treatment such as the pharmacogenomics approach.     

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.     

Differential serum proteomic analysis in a model of metabolic disease

Protein profiling would aid in better understanding the pathophysiology of metabolic disease. Here, we report on differential proteomic analysis using an animal model of diabetes mellitus and associated metabolic disorders (Otsuka Long-Evans Tokushima Fatty rat). Serum was analyzed by a new two-dimensional liquid chromatography system which separated proteins by chromatofocusing and subsequent reversed-phase chromatography. This is the first application of this approach to differential serum proteomics. Differentially expressed proteins, identified with MALDI-TOF mass spectrometry, included apolipoproteins and alpha2-HS-glycoprotein. These findings add to our understanding of the underlying pathophysiology. This new proteomic analysis is a promising tool to elucidate disease mechanisms.     

蛋白质芯片SELDI-TOFMS技术的研究进展及其在临床中的应用

蛋白质芯片为新一代的蛋白质组研究技术,由美国Ciphergen生物系统公司引进,表面增强激光解吸电离-飞行时间质谱(SELDI-TOFMS)提供一个高通量和高灵敏度的检测平台。投放至今虽短短10来年,但卓越的成果已广为医学科学界重视,尤其在恶性肿瘤的早期诊断、监控和预后研究上。蛋白质是细胞内执行生物功能的最终分子,蛋白质组学研究让人类更深入了解疾病和生命的本源,不断发现的特异性肿瘤标志物更为攻克癌症带来新希望。这里除对表面增强激光解吸电离_飞行时间质谱作较详尽的介绍外,更重点阐述其近年来蛋白质芯片近期的研究进展和在临床中的应用,并就其优劣和发展前景作出评估。     

The RAS subfamily Evolution – tracing evolution for its utmost exploitation

In the development of multicellularity, signaling proteins has played a very important role. Among them, RAS family is one of the most widely studied protein family. However, evolutionary analysis has been carried out mainly on super family level leaving sub family information in scanty. Thus, a subfamily evolutionary study on RAS evolutionary expansion is imperative as it will aid in better drug designing against dreadful diseases like Cancer and other developmental diseases. The present study was aimed to understand RAS evolution on both holistic as well as reductive level. All human RAS family genes and protein were subjected to BLAST tools to find orthologs and paralogs with different parameters followed by phylogenetic tree generation. Our results clearly showed that H-RAS is the most primitive RAS in higher eukaryotes and then diverged into other RAS family members due to different gene modification events. Furthermore, a site specific selection pressure analysis was carried out using SELECTON server which showed that H-RAS, M-RAS and N-RAS are evolving faster than K-RAS and R-RAS. Thus, the results ascertain a new ground to cancer biologists to exploit negatively selected K-RAS and R-RAS as potent drug targets in cancer therapeutics.     

Structural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery

The proteins Keap1 and Nrf2 together act as a cytoprotective mechanism that enables cells to overcome electrophilic and oxidative stress. Research has shown that manipulating this system by modulating the Keap1-Nrf2 interaction either through inhibition at the binding interface or via the covalent modification of Keap1 could provide a powerful therapeutic strategy for a range of diseases. However, despite intensive investigation of the system and significant progress in the development of inhibitory small molecules, there is still much to learn about the pathways associated with the Keap1-Nrf2 system and the structural details underpinning its mechanism of action. In this review, we discuss how a deeper understanding could prove revolutionary in the development of new inhibitors and activators as well as guiding how to best harness Keap1 for targeted protein degradation.     

The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.     

Acute or chronic? Within-host models with immune dynamics, infection outcome, and parasite evolution

There is ample theoretical and experimental evidence that virulence evolution depends on the immune response of the host. In this article, we review a number of recent studies that attempt to explicitly incorporate the dynamics of the immune system (instead of merely representing it by a single black box parameter) in models for the evolution of parasite virulence. A striking observation is that the type of infection (acute or chronic) is invariably considered to be a constraint that model assumptions have to satisfy rather than as a potential outcome of the interaction of the parasite with its host's immune system. We argue that avoiding making assumptions about the type of infection will lead to a better understanding of infectious diseases, even though a number of fundamental and technical problems remain. Dynamical modeling of the immune system opens a wide range of perspectives: for understanding how the immune system eradicates a parasite (which it does for most pathogens but not for all, HIV being a notorious example of a virus that is not completely eliminated), for studying multiple infections through concomitant immunity, for understanding the emergence and evolution of the immune system in animals, and for evolutionary epidemiology in general (e.g., predicting evolutionary consequences of new therapies and public health policies). We conclude by discussing new approaches based on embedded (or nested) models and identify future perspectives for the modeling of infectious diseases.