Non-Coding RNA in the Pathogenesis, Progression and Treatment of Hypertension.
International journal of molecular sciences
Hypertension is a complex, multifactorial disease that involves the coexistence of multiple risk factors, environmental factors and physiological systems. The complexities extend to the treatment and management of hypertension, which are still the pursuit of many researchers. In the last two decades, various genes have emerged as possible biomarkers and have become the target for investigations of specialized drug design based on its risk factors and the primary cause. Owing to the growing technology of microarrays and next-generation sequencing, the non-protein-coding RNAs (ncRNAs) have increasingly gained attention, and their status of redundancy has flipped to importance in normal cellular processes, as well as in disease progression. The ncRNA molecules make up a significant portion of the human genome, and their role in diseases continues to be uncovered. Specifically, the cellular role of these ncRNAs has played a part in the pathogenesis of hypertension and its progression to heart failure. This review explores the function of the ncRNAs, their types and biology, the current update of their association with hypertension pathology and the potential new therapeutic regime for hypertension.
10.3390/ijms19040927
The CYP/20-HETE/GPR75 axis in hypertension.
Advances in pharmacology (San Diego, Calif.)
20-Hydroxyeicosatetraenoic acid (20-HETE) is a bioactive lipid generated from the ω-hydroxylation of arachidonic acid (AA) by enzymes of the cytochrome P450 (CYP) family, primarily the CYP4A and CYP4F subfamilies. 20-HETE is most notably identified as a modulator of vascular tone, regulator of renal function, and a contributor to the onset and development of hypertension and cardiovascular disease. 20-HETE-mediated signaling promotes hypertension by sensitizing the vasculature to constrictor stimuli, inducing endothelial dysfunction, and potentiating vascular inflammation. These bioactions are driven by the activation of the G-protein coupled receptor 75 (GPR75), a 20-HETE receptor (20HR). Given the capacity of 20-HETE signaling to drive pro-hypertensive mechanisms, the CYP/20-HETE/GPR75 axis has the potential to be a significant therapeutic target for the treatment of hypertension and cardiovascular diseases associated with increases in blood pressure. In this chapter, we review 20-HETE-mediated cellular mechanisms that promote hypertension, highlight important data in humans such as genetic variants in the CYP genes that potentiate 20-HETE production and describe recent findings in humans with 20HR/GPR75 mutations. Special emphasis is given to the 20HR and respective receptor blockers that have the potential to pave a path to translational and clinical studies for the treatment of 20-HETE-driven hypertension, and obesity/metabolic syndrome.
10.1016/bs.apha.2022.02.003
New Molecules for Treating Resistant Hypertension: a Clinical Perspective.
Azzam Omar,Kiuchi Marcio G,Ho Jan K,Matthews Vance B,Gavidia Leslie Marisol Lugo,Nolde Janis M,Carnagarin Revathy,Schlaich Markus P
Current hypertension reports
PURPOSE OF REVIEW:To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions. RECENT FINDINGS:RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.
10.1007/s11906-019-0978-z
[New therapeutic targets in hypertension].
Medicina clinica
Even though a large number of antihypertensive drugs are suitable for hypertension treatment, some new therapeutic targets are recently under development. Most are focused in the treatment of resistant hypertension, added to the drugs currently available for treating such condition. Others have specific particularities in their duration of action, which allows their use once per month or every six months and could become alternatives to the current antihypertensive treatment. Most interesting therapeutic targets are the renin-angiotensin-aldosterone system, through interference with the RNA of the angiotensinogen, the inhibition of brain aminopeptidase III, the inhibition of aldosterone synthase, and new non-steroidal aldosterone receptor antagonists. In addition, dual endothelin receptor antagonists or agonists of the NPR1 receptor, the main effector of natriuretic peptides are other new interesting therapeutic possibilities. In this paper, we review clinical data on the development of the most interesting molecules acting through these new therapeutic targets.
10.1016/j.medcli.2024.03.028
microRNA-21 and hypertension.
Li Xiao,Wei Yongxiang,Wang Zuoguang
Hypertension research : official journal of the Japanese Society of Hypertension
Hypertension, a multifactorial disease, is a major risk factor for the development of stroke, coronary artery disease, heart failure, and chronic renal failure. However, its underlying cellular and molecular mechanisms remain largely elusive. Numerous studies have shown that microRNAs (miRNAs) are involved in a variety of cellular processes, including cellular proliferation, apoptosis, differentiation, and the development of diseases. microRNA-21 (miR-21), a conserved single-stranded non-coding RNA that is composed of approximately 22 nucleotides, is one of the most intensively studied miRNAs in recent years, and it can regulate gene expression at the post-transcriptional level. miR-21 is expressed in many kinds of tumors and in the cardiovascular system, and it plays an important role in the occurrence and development of cardiovascular diseases. In recent years, more and more evidence indicates that miR-21 plays an important role in hypertension. This article reviews the source, function, and altered levels of miR-21 in hypertension and the role of miR-21 in the pathogenesis of hypertension and target organ damage (TOD). The potential role of miR-21 as a new target for predicting and treating hypertension is also explored.
10.1038/s41440-018-0071-z
New and developing pharmacotherapies for hypertension.
Expert review of cardiovascular therapy
INTRODUCTION:Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED:The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION:Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.
10.1080/14779072.2022.2105204
Role of inflammation, immunity, and oxidative stress in hypertension: New insights and potential therapeutic targets.
Frontiers in immunology
Hypertension is regarded as the most prominent risk factor for cardiovascular diseases, which have become a primary cause of death, and recent research has demonstrated that chronic inflammation is involved in the pathogenesis of hypertension. Both innate and adaptive immunity are now known to promote the elevation of blood pressure by triggering vascular inflammation and microvascular remodeling. For example, as an important part of innate immune system, classically activated macrophages (M1), neutrophils, and dendritic cells contribute to hypertension by secreting inflammatory cy3tokines. In particular, interferon-gamma (IFN-γ) and interleukin-17 (IL-17) produced by activated T lymphocytes contribute to hypertension by inducing oxidative stress injury and endothelial dysfunction. However, the regulatory T cells and alternatively activated macrophages (M2) may have a protective role in hypertension. Although inflammation is related to hypertension, the exact mechanisms are complex and unclear. The present review aims to reveal the roles of inflammation, immunity, and oxidative stress in the initiation and evolution of hypertension. We envisage that the review will strengthen public understanding of the pathophysiological mechanisms of hypertension and may provide new insights and potential therapeutic strategies for hypertension.
10.3389/fimmu.2022.1098725
Are there any new pharmacologic therapies on the horizon to better treat hypertension? A state-of-the-art paper.
Habib Gabriel B,Basra Sukhdeep S
Journal of cardiovascular pharmacology and therapeutics
Hypertension is the most important cardiovascular risk factor. We have witnessed a significant improvement in hypertension treatment and control and an impressive growth in the pharmacologic options available to clinicians and hypertension specialists. With up to a third of patients with hypertension not at the recommended goal blood pressures, it is critically important to develop novel therapeutic approaches to better treat hypertension. This review will explore the ever-expanding horizon of antihypertensive treatment and will focus on 2 major areas of drug development. First, we will review novel targets for pharmacologic treatment and novel molecules and classes of drugs in various phases of development and recognize the limitations we face in their transition from research and development to clinical practice. Then, we will discuss an expanding array of combination strategies to better treat hypertension with the goal of minimizing the burden of cardiovascular and renal complications of hypertension.
10.1177/1074248414529620
Angiotensin-converting enzyme 2 as a novel target for gene therapy for hypertension.
Katovich Michael J,Grobe Justin L,Huentelman Matt,Raizada Mohan K
Experimental physiology
Less than one-third of patients with hypertension have their blood pressures (BP) controlled with current traditional therapeutic approaches for the treatment and control of hypertension. Pharmacological approaches may have reached a plateau in their effectiveness and thus newer innovative strategies need to be studied not only to increase the number of patients that can achieve BP control, but also to find a way to cure, not just manage, the disease. Continuous advances in gene delivery systems coupled with the completion of the Human Genome Project, now make it possible to investigate genetic means for the treatment and possible cure for hypertension. The renin-angiotensin system (RAS) has long been known to regulate BP, and salt and water metabolism. This system is unique in having both a peripheral circulating system and a tissue-based system. Each of these components have been ascribed a variety of physiological effects that have been associated with not only an increase in BP, but also in a variety of the pathophysiological manifestations associated with hypertension, such as cardiac hypertrophy and kidney dysfunction. We and others have used an antisense gene therapy approach, targeting the classical components of the RAS, to effectively attenuate the development of hypertension and related cardiovascular pathophysiologies in numerous experimental models of hypertension. Recently other components of the RAS have been elucidated and some of these components may be potential targets in a gene therapy approach. This article will focus on angiotensin-converting enzyme 2 (ACE2) as a new, potential target of gene therapy for hypertensive disorders.
10.1113/expphysiol.2004.028522
Characterization of musclin as a new target for treatment of hypertension.
Lin Jia-Wei,Tsai Cheng-Chia,Chen Li-Jen,Niu Ho-Shan,Chang Chen Kuei,Niu Chiang-Shan
BioMed research international
Musclin is a novel skeletal muscle-derived factor found in the signal sequence trap of mouse skeletal muscle cDNAs. Recently, it has been demonstrated that musclin is involved in the pathogenesis of spontaneously hypertensive rats (SHRs). However, it is known as a genetic hypertension model. In the present study, we aim to investigate the role of musclin in another animal model of hypertension and characterize the direct effect of musclin on vascular contraction. The results show that expression of musclin was increased in arterial tissues isolated from DOCA-salt induced hypertensive rats or the normal rats received repeated vasoconstriction with phenylephrine. Additionally, direct incubation with phenylephrine did not modify the expression of musclin in the in vitro studies. Also, the direct effect of musclin on the increase of intracellular calcium was observed in a concentration-dependent manner. These results provide the evidence to support that musclin is involved in hypertension. Thus, musclin is suitable to be considered as a novel target for treatment of hypertension.
10.1155/2014/354348
Purinergic P2Y receptors: A new therapeutic target of age-dependent hypertension.
Sunggip Caroline,Nishimura Akiyuki,Shimoda Kakeru,Numaga-Tomita Takuro,Tsuda Makoto,Nishida Motohiro
Pharmacological research
Aging has a remarkable effect on cardiovascular homeostasis and it is known as the major non-modifiable risk factor in the development of hypertension. Medications targeting sympathetic nerve system and/or renin-angiotensin-aldosterone system are widely accepted as a powerful therapeutic strategy to improve hypertension, although the control rates remain unsatisfactory especially in the elder patients with hypertension. Purinergic receptors, activated by adenine, uridine nucleotides and nucleotide sugars, play pivotal roles in many biological processes, including platelet aggregation, neurotransmission and hormone release, and regulation of cardiovascular contractility. Since clopidogrel, a selective inhibitor of G protein-coupled purinergic P2Y receptor (P2YR), achieved clinical success as an anti-platelet drug, P2YRs has been attracted more attention as new therapeutic targets of cardiovascular diseases. We have revealed that UDP-responsive P2YR promoted angiotensin type 1 receptor (AT1R)-stimulated vascular remodeling in mice, in an age-dependent manner. Moreover, the age-related formation of heterodimer between AT1R and P2YR was disrupted by MRS2578, a P2YR-selective inhibitor. These findings suggest that P2YR is a therapeutic target to prevent age-related hypertension.
10.1016/j.phrs.2017.03.013
Discovery of new sites for drug binding to the hypertension-related renin-angiotensinogen complex.
Brás Natércia F,Fernandes Pedro A,Ramos Maria J
Chemical biology & drug design
Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.
10.1111/cbdd.12258
New drug targets for hypertension: A literature review.
Gao Qiannan,Xu Li,Cai Jun
Biochimica et biophysica acta. Molecular basis of disease
Hypertension is one of the most prevalent cardiovascular diseases worldwide. However, in the population of resistant hypertension, blood pressure is difficult to control effectively. Moreover, antihypertensive drugs may have adverse effect currently. Hence, new therapeutic targets and treatments are needed to uncovered and exploited to control hypertension and its comorbidities. In the past, classical drug targets, such as the aldosterone receptor, aldosterone synthase, and ACE2/angiotensin 1-7/Mas receptor axis, have been investigated. Recently, vaccines and drugs targeting the gastrointestinal microbiome, which represent drug classes, have also been investigated for the management of blood pressure. In this review, we summarized current knowledge on classical and new drug targets and discussed the potential utility of new drugs in the treatment of hypertension.
10.1016/j.bbadis.2020.166037
Novel therapeutic targets for hypertension.
Paulis Ludovit,Unger Thomas
Nature reviews. Cardiology
Despite the existence of established, effective therapies for hypertension, new methods of blood pressure and cardiovascular risk reduction are still needed. Novel approaches are targeted towards treating resistant hypertension, improving blood-pressure control, and achieving further risk reduction beyond blood-pressure lowering. Modulation of the renin-angiotensin-aldosterone system (RAAS) provides the rationale for current antihypertensive therapies, including the relatively new agents eplerenone and aliskiren. Novel targets for antihypertensive therapy are also likely to be RAAS-related. The stimulation of angiotensin II type 2 receptors, or supplementation with renalase, could counteract the effects of angiotensin II type 1 receptor stimulation or catecholamine release. Combined angiotensin-converting-enzyme and neutral endopeptidase blockade decreases blood pressure, but is associated with a high incidence of angioedema. Aldosterone synthase inhibitors might improve tolerability in aldosterone antagonism. A (pro)renin-receptor blocker could prevent the deleterious angiotensin-independent actions of renin that are not inhibited by aliskiren. Finally, new minimally invasive surgical procedures have revived the concept of renal denervation, and could be a therapeutic option for patients with resistant hypertension. All of these strategies are exciting prospects, but which of them will prove valuable in clinical setting remains to be discovered.
10.1038/nrcardio.2010.85