ABSTRACT
OBJECTIVE: Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator. It is not known whether the pro-resolving effects of Ang-(1-7) are sustained and protect the lung from a subsequent inflammatory challenge. This study sought to investigate the impact of treatment in face of a second allergic or lipopolysaccharide (LPS) challenge. METHODS: Mice, sensitized and challenged with ovalbumin (OVA), received a single Ang-(1-7) dose at the peak of eosinophilic inflammation, 24 h after the final OVA challenge. Subsequently, mice were euthanized at 48, 72, 96, and 120 h following the OVA challenge, and cellular infiltrate, inflammatory mediators, lung histopathology, and macrophage-mediated efferocytic activity were evaluated. The secondary inflammatory stimulus (OVA or LPS) was administered 120 h after the last OVA challenge, and subsequent inflammatory analyses were performed. RESULTS: Treatment with Ang-(1-7) resulted in elevated levels of IL-10, CD4+Foxp3+, Mres in the lungs and enhanced macrophage-mediated efferocytic capacity. Moreover, in allergic mice treated with Ang-(1-7) and then subjected to a secondary OVA challenge, inflammation was also reduced. Similarly, in mice exposed to LPS, Ang-(1-7) effectively prevented the lung inflammation. CONCLUSION: A single dose of Ang-(1-7) resolves lung inflammation and protect the lung from a subsequent inflammatory challenge highlighting its potential therapeutic for individuals with asthma.
Subject(s)
Angiotensin I , Lipopolysaccharides , Lung , Ovalbumin , Peptide Fragments , Animals , Angiotensin I/therapeutic use , Angiotensin I/pharmacology , Angiotensin I/administration & dosage , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Peptide Fragments/administration & dosage , Lung/drug effects , Lung/pathology , Lung/immunology , Ovalbumin/immunology , Mice , Male , Macrophages/drug effects , Macrophages/immunology , Eosinophils/drug effects , Eosinophils/immunology , Mice, Inbred BALB C , Inflammation/drug therapy , Eosinophilia/drug therapy , Eosinophilia/immunology , Bronchoalveolar Lavage Fluid/immunology , Bronchoalveolar Lavage Fluid/cytologyABSTRACT
BACKGROUND: Alterations in the renin-angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1-7 (Ang-(1-7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1-7) infusion on the development and severity of septic shock. METHODS: This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1-7) (n = 7) or placebo (n = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. RESULTS: There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1-7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 µg/kg/min in the Ang-(1-7) group compared to 4.3 µg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1-7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO2/FiO2 ratio were higher in the Ang-(1-7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1-7) group compared to 7.4 mmol/L in the control group. CONCLUSIONS: In this experimental septic shock model, early Ang-(1-7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.
Subject(s)
Sepsis , Shock, Septic , Animals , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Norepinephrine/pharmacology , Norepinephrine/therapeutic use , Sepsis/drug therapy , SheepABSTRACT
Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting enzyme type 2 (ACE2). Using osmotic minipumps, infusion of Ang-(1-9) consistently reduces blood pressure in several rat hypertension models. In these animals, hypertension-induced end-organ damage is also decreased. Several pieces of evidence suggest that Ang-(1-9) is the endogenous ligand that binds and activates the type-2 angiotensin II receptor (AT2R). Activation of AT2R triggers different tissue-specific signaling pathways. This phenomenon could be explained by the ability of AT2R to form different heterodimers with other G protein-coupled receptors. Because of the antihypertensive and protective effects of AT2R activation by Ang-(1-9), associated with a short half-life of RAS peptides, several synthetic AT2R agonists have been synthesized and assayed. Some of them, particularly CGP42112, C21 and novokinin, have demonstrated antihypertensive properties. Only two synthetic AT2R agonists, C21 and LP2-3, have been tested in clinical trials, but none of them like an antihypertensive. Therefore, Ang-(1-9) is a promising antihypertensive drug that reduces hypertension-induced end-organ damage. However, further research is required to translate this finding successfully to the clinic.
Subject(s)
Angiotensin I , Hypertension , Angiotensin I/metabolism , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Angiotensin II/metabolism , Animals , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Imidazoles , Peptidyl-Dipeptidase A/metabolism , Rats , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/agonists , Renin-Angiotensin System , Sulfonamides , ThiophenesABSTRACT
Infectious diseases, once believed to be an eradicable public health threat, still represent a leading cause of death worldwide. Environmental and social changes continuously favor the emergence of new pathogens and rapid dissemination around the world. The limited availability of anti-viral therapies and increased antibiotic resistance has made the therapeutic management of infectious disease a major challenge. Inflammation is a primordial defense to protect the host against invading microorganisms. However, dysfunctional inflammatory responses contribute to disease severity and mortality during infections. In recent years, a few studies have examined the relevance of resolution of inflammation in the context of infections. Inflammation resolution is an active integrated process transduced by several pro-resolving mediators, including Annexin A1 and Angiotensin-(1-7). Here, we examine some of the cellular and molecular circuits triggered by pro-resolving molecules and that may be beneficial in the context of infectious diseases.
Subject(s)
Annexin A1 , Communicable Diseases , Humans , Annexin A1/therapeutic use , Angiotensin I/therapeutic use , Inflammation/drug therapy , Inflammation Mediators/therapeutic use , Communicable Diseases/drug therapyABSTRACT
BACKGROUND: Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by muscle weakness, loss of muscle mass, and decline in the capacity of force generation. Aging can cause sarcopenia. Several therapeutic strategies have been evaluated to prevent or alleviate this disorder. One of them is angiotensin 1-7 [Ang-(1-7)], an anti-atrophic peptide for skeletal muscles that regulates decreased muscle mass for several causes, including aging. Another regulator of muscle mass and function is andrographolide, a bicyclic diterpenoid lactone that decreases the nuclear factor kappa B (NF-κB) signaling and attenuates the severity of some muscle diseases. OBJECTIVE: Evaluate the effect of combined administration of Ang-(1-7) with andrographolide on the physical performance, muscle strength, and fiber´s diameter in a murine model of sarcopenia by aging. METHODS: Aged male mice of the C57BL/6J strain were treated with Andrographolide, Ang-(1-7), or combined for three months. The physical performance, muscle strength, and fiber´s diameter were measured. RESULTS: The results showed that aged mice (24 months old) treated with Ang-(1-7) or Andrographolide improved their performance on a treadmill test, muscle strength, and their fiber´s diameter compared to aged mice without treatment. The combined administration of Ang-(1-7) with andrographolide to aged mice has an enhanced synergically effect on physical performance, muscle strength, and fiber´s diameter. CONCLUSION: Our results indicated that in aged mice, the effects of andrographolide and Ang-(1-7) on muscle function, strength, and fiber´s diameter are potentiated.
Subject(s)
Diterpenes , Muscular Diseases , Sarcopenia , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Animals , Diterpenes/pharmacology , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal , Muscular Diseases/drug therapy , Muscular Diseases/pathology , Peptide Fragments , Sarcopenia/drug therapy , Sarcopenia/pathologyABSTRACT
BACKGROUND: Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1-7 (Ang-(1-7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1-7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. METHODS: VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1-7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05. RESULTS: Treatment with Ang-(1-7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. CONCLUSIONS: These data show that treatment with Ang-(1-7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.
Subject(s)
Angiotensin I/agonists , Angiotensin I/metabolism , Cognitive Dysfunction/metabolism , Cytokines/metabolism , Dementia, Vascular/metabolism , Neurofilament Proteins/metabolism , Peptide Fragments/agonists , Peptide Fragments/metabolism , Angiotensin I/therapeutic use , Animals , Biomarkers/metabolism , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/pathology , Dementia, Vascular/drug therapy , Dementia, Vascular/pathology , Male , Mice , Mice, Inbred C57BL , Peptide Fragments/therapeutic use , Prognosis , Stroke Volume/physiologyABSTRACT
Brain renin-angiotensin (Ang) system (RAS) is implicated in neuroinflammation, a major characteristic of aging process. Angiotensin (Ang) II, produced by angiotensin-converting enzyme (ACE), activates immune system via angiotensin type 1 receptor (AT1), whereas Ang(1-7), generated by ACE2, binds with Mas receptor (MasR) to restrain excessive inflammatory response. Therefore, the present study aims to explore the relationship between RAS and neuroinflammation. We found that repeated lipopolysaccharide (LPS) treatment shifted the balance between ACE/Ang II/AT1 and ACE2/Ang(1-7)/MasR axis to the deleterious side and treatment with either MasR agonist, AVE0991 (AVE) or ACE2 activator, diminazene aceturate, exhibited strong neuroprotective actions. Mechanically, activation of ACE2/Ang(1-7)/MasR axis triggered the Forkhead box class O1 (FOXO1)-autophagy pathway and induced superoxide dismutase (SOD) and catalase (CAT), the FOXO1-targeted antioxidant enzymes. Meanwhile, knockdown of MasR or FOXO1 in BV2 cells, or using the selective FOXO1 inhibitor, AS1842856, in animals, suppressed FOXO1 translocation and compromised the autophagic process induced by MasR activation. We further used chloroquine (CQ) to block autophagy and showed that suppressing either FOXO1 or autophagy abrogated the anti-inflammatory action of AVE. Likewise, Ang(1-7) also induced FOXO1 signaling and autophagic flux following LPS treatment in BV2 cells. Cotreatment with AS1842856 or CQ all led to autophagic inhibition and thereby abolished Ang(1-7)-induced remission on NLRP3 inflammasome activation caused by LPS exposure, shifting the microglial polarization from M1 to M2 phenotype. Collectively, these results firstly illustrated the mechanism of ACE2/Ang(1-7)/MasR axis in neuroinflammation, strongly indicating the involvement of FOXO1-mediated autophagy in the neuroimmune-modulating effects triggered by MasR activation.
Subject(s)
Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2/therapeutic use , Autophagy/drug effects , Microglia/drug effects , Neuroinflammatory Diseases/drug therapy , Peptide Fragments/therapeutic use , Angiotensin I/pharmacology , Angiotensin-Converting Enzyme 2/pharmacology , Animals , Humans , Mice , Neuroinflammatory Diseases/genetics , Peptide Fragments/pharmacology , Signal Transduction , TransfectionABSTRACT
Cardiovascular diseases are the principal cause of death worldwide, with hypertension being the most common cardiovascular disease risk factor. High blood pressure (BP) is also associated with an increased risk of poor cognitive performance and dementia including Alzheimer's disease. Angiotensin 1-7 (Ang 1-7), a product of the renin-angiotensin system (RAS), exhibits central and peripheral actions to reduce BP. Recent data from our lab reveals that the addition of a non-radioactive iodine molecule to the tyrosine in position 4 of Ang 1-7 (iodoAng 1-7) makes it ~1000-fold more potent than Ang 1-7 in competing for the 125 I-Ang 1-7 binding site (Stoyell-Conti et al., 2020). Moreover, the addition of the non-radioactive iodine molecule increases (~4-fold) iodoAng 1-7's ability to bind to the AT1 receptor (AT1R), the primary receptor for Ang II. Preliminary data indicates that iodoAng 1-7 can also compete for the 125 I-Ang IV binding site with a low micromolar IC50. Thus, our aims were to compare the effects of chronic treatment of the Spontaneously Hypertensive Rat (SHR) with iodoAng 1-7 (non-radioactive iodine isotope) and Ang 1-7 on arterial pressure, heart rate, and cognitive function. For this study, male SHRs were divided into three groups and treated with Saline, Ang 1-7, or iodoAng 1-7 administrated subcutaneously using a 28-day osmotic mini pump. Systolic BP was measured non-invasively by the tail-cuff technique. Cognitive function was assessed by Y-Maze test and novel object recognition (NOR) test. We have demonstrated in SHRs that subcutaneous administration of high doses of iodoAng 1-7 prevented the increase in heart rate with age, while Ang 1-7 showed a trend toward preventing the increase in heart rate, possibly by improving baroreflex control of the heart. Conversely, neither Ang 1-7 nor iodoAng 1-7 administered subcutaneously affected BP nor cognitive function.
Subject(s)
Angiotensin I/therapeutic use , Blood Pressure , Cognition , Heart Rate , Hypertension/drug therapy , Peptide Fragments/therapeutic use , Angiotensin I/administration & dosage , Angiotensin I/pharmacokinetics , Animals , Iodine Radioisotopes , Male , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacokinetics , Protein Binding , Rats , Rats, Inbred SHR , Receptor, Angiotensin, Type 1/metabolismABSTRACT
The in vivo application and efficacy of many therapeutic peptides is limited because of their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classic and protective arms. The balance between these two arms is critical for the homeostasis of the body's physiologic function. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathologic conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of angiotensin-(1-7) [Ang-(1-7)], a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings. SIGNIFICANCE STATEMENT: Ang-(1-7) is a unique peptide component of the renin-angiotensin system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.
Subject(s)
Angiotensin I/pharmacology , Antihypertensive Agents/pharmacology , Hypoglycemic Agents/pharmacology , Peptide Fragments/pharmacology , Renin-Angiotensin System/drug effects , Angiotensin I/administration & dosage , Angiotensin I/therapeutic use , Animals , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Drug Delivery Systems , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Peptide Fragments/administration & dosage , Peptide Fragments/therapeutic useABSTRACT
Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.
Subject(s)
Angiotensin I/administration & dosage , Angiotensin I/therapeutic use , Endotoxemia/drug therapy , Hypotension/drug therapy , Peptide Fragments/administration & dosage , Peptide Fragments/therapeutic use , Vasopressins/metabolism , Animals , Endotoxemia/blood , Endotoxemia/complications , Endotoxemia/genetics , Gene Expression Regulation , Hypotension/blood , Hypotension/complications , Hypotension/genetics , Inflammation/blood , Inflammation/complications , Inflammation/pathology , Lactic Acid/blood , Lactic Acid/metabolism , Lipopolysaccharides , Male , Osmolar Concentration , Proto-Oncogene Mas , Proto-Oncogene Proteins/metabolism , Rats, Wistar , Receptors, G-Protein-Coupled/metabolism , Sodium/blood , Vasopressins/geneticsABSTRACT
OBJECTIVE: To observe the effects of angiotensin-(1-7) (Ang-(1-7)) on glucose metabolism, islet function and insulin resistance in a rat model of streptozotocin-induced diabetes mellitus (DM) and investigate its mechanism. METHODS: Thirty-four male Wistar rats were randomly divided into 3 groups: control group, which was fed a standard diet, DM group, high-fat diet and injected with streptozotocin, and Ang-(1-7) group receiving an injection of streptozotocin followed by Ang-(1-7) treatment. Blood glucose level, fasting serum Ang II and insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. The pancreases were collected for histological examination, protein and gene expression analysis. RESULTS: Compared with the control group, fasting blood glucose, serum angiotensin II level, and HOMA-IR value increased, while serum insulin level decreased in the DM group. Moreover, islet structure was damaged, ß cells were irregularly arranged, the cytoplasm was loose in the DM group. Expressions of Pancreatic duodenal homeobox-1 (Pdx1), glucose transporter-2 (Glut2) and glucokinase (Gk) were significantly decreased in the DM group compared with the control group. However, the DM-associated changes were dramatically reversed following Ang-(1-7) treatment. CONCLUSION: Ang-(1-7) protects against streptozotocin-induced DM through the improvement of insulin secretion, insulin resistance and islet fibrosis, which is associated with the upregulation of Pdx1, Glut2 and Gk expressions.
Subject(s)
Angiotensin I/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Islets of Langerhans/drug effects , Peptide Fragments/pharmacology , Angiotensin I/therapeutic use , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Glucose Transporter Type 2/genetics , Glucose Transporter Type 2/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Islets of Langerhans/physiology , Male , Peptide Fragments/therapeutic use , Rats , Rats, Wistar , Streptozocin , Trans-Activators/genetics , Trans-Activators/metabolism , Up-Regulation/drug effects , Up-Regulation/geneticsABSTRACT
Resolution failure of exacerbated inflammation triggered by Influenza A virus (IAV) prevents return of pulmonary homeostasis and survival, especially when associated with secondary pneumococcal infection. Therapeutic strategies based on pro-resolving molecules have great potential against acute inflammatory diseases. Angiotensin-(1-7) [Ang-(1-7)] is a pro-resolving mediator that acts on its Mas receptor (MasR) to promote resolution of inflammation. We investigated the effects of Ang-(1-7) and the role of MasR in the context of primary IAV infection and secondary pneumococcal infection and evaluated pulmonary inflammation, virus titers and bacteria counts, and pulmonary damage. Therapeutic treatment with Ang-(1-7) decreased neutrophil recruitment, lung injury, viral load and morbidity after a primary IAV infection. Ang-(1-7) induced apoptosis of neutrophils and efferocytosis of these cells by alveolar macrophages, but had no direct effect on IAV replication in vitro. MasR-deficient (MasR-/-) mice were highly susceptible to IAV infection, displaying uncontrolled inflammation, increased viral load and greater lethality rate, as compared to WT animals. Ang-(1-7) was not protective in MasR-/- mice. Interestingly, Ang-(1-7) given during a sublethal dose of IAV infection greatly reduced morbidity associated with a subsequent S. pneumoniae infection, as seen by decrease in the magnitude of neutrophil influx, number of bacteria in the blood leading to a lower lethality. Altogether, these results show that Ang-(1-7) is highly protective against severe primary IAV infection and protects against secondary bacterial infection of the lung. These effects are MasR-dependent. Mediators of resolution of inflammation, such as Ang-(1-7), should be considered for the treatment of pulmonary viral infections.
Subject(s)
Angiotensin I/therapeutic use , Anti-Inflammatory Agents/therapeutic use , Peptide Fragments/therapeutic use , Pneumococcal Infections/drug therapy , Pneumonia, Viral/drug therapy , Proto-Oncogene Proteins/immunology , Receptors, G-Protein-Coupled/immunology , A549 Cells , Angiotensin I/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/immunology , Dogs , Humans , Influenza A virus , Lung/drug effects , Lung/immunology , Lung/pathology , Madin Darby Canine Kidney Cells , Male , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/drug effects , Neutrophils/immunology , Peptide Fragments/pharmacology , Peroxidase/immunology , Phagocytosis/drug effects , Pneumococcal Infections/immunology , Pneumococcal Infections/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Proto-Oncogene Mas , Proto-Oncogene Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Streptococcus pneumoniaeABSTRACT
In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).
Subject(s)
Angiotensin I/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/complications , Peptide Fragments/therapeutic use , Pneumonia, Viral/complications , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/virology , Angiotensin I/physiology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/mortality , Humans , Pandemics , Peptide Fragments/physiology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2ABSTRACT
The ongoing COVID-19 pandemic has produced serious turmoil world-wide. Lung injury causing acute respiratory distress syndrome seems to be a most dreaded complication occurring in â¼30%. Older patients with cardiovascular comorbidities and acute respiratory distress syndrome have an increased mortality. Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system seems to be pivotal. In this context, angiotensin-converting enzyme 2 (ACE2), an angiotensin-converting enzyme homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions. Thus, concern was raised that the use of renin-angiotensin system inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID-19 virus. However, current data have appeased such concerns because there has been no clinical evidence of a harmful effect of these agents as based on observational studies. However, properly designed future studies will be needed to further confirm or refute current evidence. Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, whereas, in the same context, specific bradykinin inhibitors may also negate bradykinin's harmful effects. Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies. These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.
Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects , Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Humans , Pandemics , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/therapeutic use , Recombinant Proteins/therapeutic use , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
The renin-angiotensin system, one of the main regulators of vascular function, controls vasoconstriction, inflammation and vascular remodeling. Antagonistic actions of the counter-regulatory renin-angiotensin system, which include vasodilation, anti-proliferative, anti-inflammatory and anti-remodeling effects, have also been described. However, little is known about the direct effects of angiotensin-(1-9), a peptide of the counter-regulatory renin-angiotensin system, on vascular smooth muscle cells. Here, we studied the anti-vascular remodeling effects of angiotensin-(1-9), with special focus on the control of vascular smooth muscle cell phenotype. Angiotensin-(1-9) decreased blood pressure and aorta media thickness in spontaneously hypertensive rats. Reduction of media thickness was associated with decreased vascular smooth muscle cell proliferation. In the A7r5 VSMC cell line and in primary cultures of rat aorta smooth muscle cells, angiotensin-(1-9) did not modify basal proliferation. However, angiotensin-(1-9) inhibited proliferation, migration and contractile protein decrease induced by platelet derived growth factor-BB. Moreover, angiotensin-(1-9) reduced Akt and FoxO1 phosphorylation at 30 min, followed by an increase of total FoxO1 protein content. Angiotensin-(1-9) effects were blocked by the AT2R antagonist PD123319, Akt-Myr overexpression and FoxO1 siRNA. These data suggest that angiotensin-(1-9) inhibits vascular smooth muscle cell dedifferentiation by an AT2R/Akt/FoxO1-dependent mechanism.
Subject(s)
Angiotensin I/pharmacology , Antihypertensive Agents/pharmacology , Cell Dedifferentiation/drug effects , Muscle, Smooth, Vascular/drug effects , Nerve Tissue Proteins/antagonists & inhibitors , Vascular Remodeling/drug effects , Angiotensin I/therapeutic use , Animals , Antihypertensive Agents/therapeutic use , Cell Dedifferentiation/physiology , Cell Line , Hypertension/drug therapy , Hypertension/metabolism , Male , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Nerve Tissue Proteins/metabolism , Rats , Rats, Inbred SHR , Rats, Wistar , Vascular Remodeling/physiologyABSTRACT
As progressive organ shortage in cardiac transplantation demands extension of donor criteria, effort is needed to optimize graft survival. Reactive oxygen and nitrogen species, generated during organ procurement, transplantation, and reperfusion, contribute to acute and late graft dysfunction. The combined application of diverse substances acting via different molecular pathways appears to be a reasonable approach to face the complex mechanism of ischemia reperfusion injury. Thus, an antioxidant solution containing α-ketoglutaric acid, 5-hydroxymethylfurfural, N-acetyl-L-methionine, and N-acetyl-selenium-L-methionine was combined with endogenous angiotensin-(1-7). Its capacity of myocardial protection was investigated in isolated Langendorff-perfused rat hearts subjected to warm and cold ischemia. The physiological cardiac parameters were assessed throughout the experiments. Effects were evaluated via determination of the oxidative stress parameters malondialdehyde and carbonyl proteins as well as immunohistochemical and ultrastructural tissue analyses. It was shown that a combination of 20% (v/v) antioxidant solution and 220 pM angiotensin-(1-7) led to the best results with a preservation of heart tissue against oxidative stress and morphological alteration. Additionally, immediate cardiac recovery (after warm ischemia) and normal physiological performance (after cold ischemia) were recorded. Overall, the results of this study indicate substantial cardioprotection of the novel combination with promising prospective for future clinical use.
Subject(s)
Angiotensin I/therapeutic use , Antioxidants/therapeutic use , Heart/drug effects , Peptide Fragments/therapeutic use , Angiotensin I/pharmacology , Animals , Antioxidants/pharmacology , Disease Models, Animal , Male , Peptide Fragments/pharmacology , RatsABSTRACT
Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy and is often refractory to pharmacological treatment. In this scenario, extensive research has identified components of the renin-angiotensin system (RAS) as potential therapeutic targets. Therefore, the aim of the present study was to evaluate the effects of long-term treatment with angiotensin-(1-7) [Ang-(1-7)] in male Wistar rats with TLE induced by pilocarpine (PILO). Rats with TLE were submitted to intracerebroventricular (icv) infusion of Ang-(1-7) (200 ng/kg/h) for 28 days, starting at the first spontaneous motor seizure (SMS). Body weight, food intake, and SMS were evaluated daily. Behavioral tests and hippocampal protein levels were also evaluated at the end of the treatment. Ang-(1-7) treatment reduced the frequency of SMS and attenuated low anxiety levels, increased locomotion/exploration, and reduced body weight gain that was induced by TLE. Moreover, Ang-(1-7) positively regulated the hippocampal levels of antioxidant protein catalase and antiapoptotic protein B-cell lymphoma 2 (Bcl-2), as well as mammalian target of rapamycin (mTOR) phosphorylation, which were reduced by TLE. The hippocampal up-regulation of angiotensin type 1 receptor induced by TLE was also attenuated by Ang-(1-7), while the Mas receptor (MasR) was down-regulated compared with epilepsy. These data show that Ang-(1-7) presents an antiepileptic effect, increasing neuroprotection markers and reducing SMS frequency, body weight, and behavior impairments found in TLE. Therefore, Ang-(1-7) is a promising coadjutant therapeutic option for the treatment of TLE.
Subject(s)
Angiotensin I/therapeutic use , Anticonvulsants/administration & dosage , Anticonvulsants/therapeutic use , Epilepsy, Temporal Lobe/drug therapy , Peptide Fragments/therapeutic use , Angiotensin I/pharmacology , Animals , Anticonvulsants/pharmacology , Anxiety/physiopathology , Disease Models, Animal , Elevated Plus Maze Test , Epilepsy, Temporal Lobe/physiopathology , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/physiopathology , Infusions, Intraventricular , Male , Motor Activity/drug effects , Peptide Fragments/pharmacology , Photoperiod , Rats, Wistar , Weight Gain/drug effectsABSTRACT
Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19 Drug Treatment , Inflammation/drug therapy , Acetates/therapeutic use , Angiotensin I/therapeutic use , Animals , Annexin A1/therapeutic use , COVID-19/immunology , Disease Models, Animal , Docosahexaenoic Acids/therapeutic use , Humans , Hydrogen Peroxide/therapeutic use , Inflammation/immunology , Inflammation Mediators/immunology , Mice , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/immunology , Oxidants/therapeutic use , Peptide Fragments/therapeutic use , Peptides/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Rolipram/therapeutic use , Vasodilator Agents/therapeutic useABSTRACT
After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.
Subject(s)
Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , Coronavirus Infections/drug therapy , Janus Kinases/genetics , Methotrexate/therapeutic use , Pandemics , Peptide Fragments/therapeutic use , Pneumonia, Viral/drug therapy , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Progression , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/immunology , Molecular Targeted Therapy/methods , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Purines , Pyrazoles , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/immunology , SARS-CoV-2 , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.