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Current Hypertension Reports Feb 2014The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The... (Review)
Review
The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT1 receptor (AT1R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes AT2-receptors and Mas receptors (AT2R and MasR) and is characterized by effects different from and often opposing those of the AT1R. These include anti-inflammation, anti-fibrosis, anti-apoptosis and neuroregeneration that can counterbalance pathological processes and enable recovery from disease. The recent development of novel, small-molecule AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications.
Topics: Animals; Disease Models, Animal; Humans; Hypertension; Proto-Oncogene Mas; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction
PubMed: 24414230
DOI: 10.1007/s11906-013-0416-6 -
Cardiovascular Drugs and Therapy Oct 2011The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, water-salt balance and the pathogenesis of cardiovascular diseases. Angiotensin... (Review)
Review
The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, water-salt balance and the pathogenesis of cardiovascular diseases. Angiotensin II (Ang II) is the physiologically active mediator and mediates the main pathophysiological actions in RAS. Ang II exerts the effects by activating its receptors, primarily type 1 (AT1R) and type 2 (AT2R). Most of the known pathophysiological effects of Ang II are mediated by AT1R activation. The precise physiological function of AT2R is still not clear. Generally, AT2R is considered to oppose the effects of AT1R. Lectin-like oxidized low-density lipoprotein scavenger receptor-1 (LOX-1) is one of the major receptors responsible for binding, internalizing and degrading ox-LDL. The activation of LOX-1 has been known to be related to many pathophysiological events, including endothelial dysfunction and injury, fibroblast growth, and vascular smooth muscle cell hypertrophy. Many of these alterations are present in atherosclerosis, hypertension, and myocardial ischemia and remodeling. A growing body of evidence suggests the existence of a cross-talk between LOX-1 and Ang II receptors. Their interplays are embodied in the reciprocal regulation of their expression and activity. Their interplays are involved in a series of signals. Recent studies suggests that reactive oxygen species (ROS), nitric oxide (NO), protein kinase C (PKC) and mitogen activated protein kinases (MAPKs) are important signals responsible for their cross-talk. This paper reviews these aspects of dyslipidemia and RAS activation.
Topics: Animals; Dyslipidemias; Humans; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Scavenger Receptors, Class E
PubMed: 21861069
DOI: 10.1007/s10557-011-6331-7 -
Journal of the... Jun 2000The advent of specific angiotensin II (Ang II) receptor blockers (ARBs) some ten years ago has provided substantial information on the specific actions of the AT1- and... (Review)
Review
The advent of specific angiotensin II (Ang II) receptor blockers (ARBs) some ten years ago has provided substantial information on the specific actions of the AT1- and AT2-receptors. Most of the early research concentrated on the AT1-receptor, and the actions and biological roles of the AT2-receptor are much less well characterised. The AT2-receptor is involved in the inhibition of cell proliferation, and in cell differentiation and development, regeneration and apoptosis. By raising local Ang II concentrations at the AT2-receptor, selective blocking of the AT1-receptor may therefore have beneficial effects. This concept may be important for antihypertensive therapy and in cardiovascular disease in general.
Topics: Angiotensin II Type 1 Receptor Blockers; Cell Differentiation; Cell Proliferation; Humans; Hydrogen-Ion Concentration; Hypertension; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2
PubMed: 17199211
DOI: 10.3317/jraas.2000.057 -
Advances in Pharmacology (San Diego,... 2014The pathophysiological actions of the renin-angiotensin system hormone, angiotensin II (AngII), are mainly mediated by the AngII type 1 (AT1) receptor, a GPCR. The... (Review)
Review
The pathophysiological actions of the renin-angiotensin system hormone, angiotensin II (AngII), are mainly mediated by the AngII type 1 (AT1) receptor, a GPCR. The intrinsic spontaneous activity of the AT1 receptor in native tissues is difficult to detect due to its low expression levels. However, factors such as the membrane environment, interaction with autoantibodies, and mechanical stretch are known to increase G protein signaling in the absence of AngII. Naturally occurring and disease-causing activating mutations have not been identified in AT1 receptor. Constitutively active mutants (CAMs) of AT1 receptor have been engineered using molecular modeling and site-directed mutagenesis approaches among which substitution of Asn(111) in the transmembrane helix III with glycine or serine results in the highest basal activity of the receptor. Transgenic animal models expressing the CAM AT1 receptors that mimic various in vivo disease conditions have been useful research tools for discovering the pathophysiological role of AT1 receptor and evaluating the therapeutic potential of inverse agonists. This chapter summarizes the studies on the constitutive activity of AT1 receptor in recombinant as well as physiological systems. The impact of the availability of CAM AT1 receptors on our understanding of the molecular mechanisms underlying receptor activation and inverse agonism is described.
Topics: Animals; Biomedical Research; Drug Discovery; Drug Inverse Agonism; Humans; Mutation; Receptor, Angiotensin, Type 1
PubMed: 24931196
DOI: 10.1016/B978-0-12-417197-8.00006-7 -
Journal of the American Heart... Sep 2023Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the...
Background The renin-angiotensin system plays a crucial role in human physiology, and its main hormone, angiotensin, activates 2 G-protein-coupled receptors, the angiotensin type-1 and type-2 receptors, in almost every organ. However, controversy exists about the location, distribution, and expression levels of these receptors. Concerns have been raised over the low sensitivity, low specificity, and large variability between lots of commercially available antibodies for angiotensin type-1 and type-2 receptors, which makes it difficult to reconciliate results of different studies. Here, we describe the first non-antibody-based sensitive and specific targeted quantitative mass spectrometry assay for angiotensin receptors. Methods and Results Using a technique that allows targeted analysis of multiple peptides across multiple samples in a single mass spectrometry analysis, known as TOMAHAQ (triggered by offset, multiplexed, accurate mass, high resolution, and absolute quantification), we have identified and validated specific human tryptic peptides that permit identification and quantification of angiotensin type-1 and type-2 receptors in biological samples. Several peptide sequences are conserved in rodents, making these mass spectrometry assays amenable to both preclinical and clinical studies. We have used this method to quantify angiotensin type-1 and type-2 receptors in postmortem frontal cortex samples of older adults (n=28) with Alzheimer dementia. We correlated levels of angiotensin receptors to biomarkers classically linked to renin-angiotensin system activation, including oxidative stress, inflammation, amyloid-β load, and paired helical filament-tau tangle burden. Conclusions These robust high-throughput assays will not only catalyze novel mechanistic studies in the angiotensin research field but may also help to identify patients with an unbalanced angiotensin receptor distribution who would benefit from angiotensin receptor blocker treatment.
Topics: Humans; Aged; Angiotensins; Receptors, Angiotensin; Renin-Angiotensin System; Angiotensin Receptor Antagonists; Antibodies
PubMed: 37681524
DOI: 10.1161/JAHA.123.030791 -
Progress in Neurobiology Feb 2008The renin-angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure, cyclicity of reproductive... (Review)
Review
The renin-angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure, cyclicity of reproductive hormones and sexual behaviors, and the regulation of pituitary gland hormones. These functions appear to be mediated by the angiotensin II (AngII)/AT(1) receptor subtype system. More recently, the angiotensin IV (AngIV)/AT(4) receptor subtype system has been implicated in cognitive processing, cerebroprotection, local blood flow, stress, anxiety and depression. There is accumulating evidence to suggest an inhibitory influence by AngII acting at the AT(1) subtype, and a facilitory role by AngIV acting at the AT(4) subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning, and memory. This review initially describes the biochemical pathways that permit synthesis and degradation of active angiotensin peptides and three receptor subtypes (AT(1), AT(2) and AT(4)) thus far characterized. There is vigorous debate concerning the identity of the most recently discovered receptor subtype, AT(4). Descriptions of classic and novel physiologies and behaviors controlled by the RAS are presented. This review concludes with a consideration of the emerging therapeutic applications suggested by these newly discovered functions of the RAS.
Topics: Animals; Humans; Receptors, Angiotensin; Renin-Angiotensin System
PubMed: 18160199
DOI: 10.1016/j.pneurobio.2007.10.009 -
Journal of Immunology (Baltimore, Md. :... Sep 2007Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal... (Review)
Review
Preeclampsia is a pregnancy-induced hypertensive disorder that causes substantial maternal and fetal morbidity and mortality. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Recent studies indicate that women with preeclampsia have autoantibodies that activate the angiotensin receptor, AT1, and that autoantibody-mediated receptor activation contributes to pathophysiology associated with preeclampsia. The research reviewed here raises the intriguing possibility that preeclampsia may be a pregnancy-induced autoimmune disease.
Topics: Animals; Autoantibodies; Autoimmune Diseases; Female; Humans; Pre-Eclampsia; Pregnancy; Receptor, Angiotensin, Type 1
PubMed: 17785770
DOI: 10.4049/jimmunol.179.6.3391 -
Journal of Experimental Therapeutics &... Sep 2017The renin-angiotensin system, through its type 1 and type 2 angiotensin receptors (AT1R and AT2R, respectively) may have a role in prostate cancer. The objective of this...
The renin-angiotensin system, through its type 1 and type 2 angiotensin receptors (AT1R and AT2R, respectively) may have a role in prostate cancer. The objective of this pilot study was to explore that potential role by determining whether the AT1R blocker, losartan, would reduce the growth of LAPC-4 prostate cancer xenografts in nude mice. We also evaluated the tumor growth effects of using angiotensin II to activate both AT1R and AT2R simultaneously. Our data showed that losartan decreased tumor volumes by 56% versus control. This decrease reached statistical significance at day 54 (p = 0.0014). By day 54, Ki67 was also reduced in the losartan group, though not significantly so (p = 0.077). Losartan had no significant effect on AT1R or AT2R expression. Despite significant increases in both AT1R and AT2R at day 29 (p = 0.043 and 0.038, respectively), the administration of angiotensin II did not result in any significant differences in tumor volumes or ki67 at any time point. These data suggest that selective activation and induction of AT2R coupled with blockade of AT1R may slow prostate cancer growth. Future larger studies are needed to confirm these results.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Cell Line, Tumor; Losartan; Male; Mice; Neoplasm Transplantation; Prostatic Neoplasms; RNA, Messenger; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Signal Transduction; Transcriptome; Tumor Burden; Vasoconstrictor Agents
PubMed: 28976133
DOI: No ID Found -
International Journal of Molecular... Jun 2022This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT receptors (ATRs) by angiotensin II (Ang... (Review)
Review
This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT receptors (ATRs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB receptors (CBRs), modify the response to ATR stimulation. CBR blockade may enhance ATR-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CBRs and ATRs induces opposite or the same effects. Second, CBR blockade may diminish ATR levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II-AT receptor system or angiotensin 1-7-Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of ATR-CBR heteromerization. As a therapeutic consequence, CBR antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.
Topics: Angiotensin II; COVID-19; Cannabinoids; Endocannabinoids; Humans; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Cannabinoid; Renin; Renin-Angiotensin System
PubMed: 35683028
DOI: 10.3390/ijms23116350 -
Cells May 2020The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system... (Review)
Review
The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1-7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC.
Topics: Angiotensin I; Angiotensin II; Breast Neoplasms; Female; Humans; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System
PubMed: 32471115
DOI: 10.3390/cells9061336