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1.
Artigo em Inglês | MEDLINE | ID: mdl-34925551

RESUMO

The RAS (renin-angiotensin system) is the part of the endocrine system that plays a prime role in the control of essential hypertension. Since the discovery of brain RAS in the seventies, continuous efforts have been put by the scientific committee to explore it more. The brain has shown the presence of various components of brain RAS such as angiotensinogen (AGT), converting enzymes, angiotensin (Ang), and specific receptors (ATR). AGT acts as the precursor molecule for Ang peptides-I, II, III, and IV-while the enzymes such as prorenin, ACE, and aminopeptidases A and N synthesize it. AT1, AT2, AT4, and mitochondrial assembly receptor (MasR) are found to be plentiful in the brain. The brain RAS system exhibits pleiotropic properties such as neuroprotection and cognition along with regulation of blood pressure, CVS homeostasis, thirst and salt appetite, stress, depression, alcohol addiction, and pain modulation. The molecules acting through RAS predominantly ARBs and ACEI are found to be effective in various ongoing and completed clinical trials related to cognition, memory, Alzheimer's disease (AD), and pain. The review summarizes the recent advances in the brain RAS system highlighting its significance in pathophysiology and treatment of the central nervous system-related disorders.


Assuntos
Preparações Farmacêuticas , Sistema Renina-Angiotensina , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Pressão Sanguínea , Encéfalo
2.
Sovrem Tekhnologii Med ; 12(6): 98-108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796023

RESUMO

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS). The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2. Results: By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.The second participant in the pathogenesis of brain damage in COVID-19 is CD147 - the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Basigina , Humanos , Fragmentos de Peptídeos/metabolismo , Serina Endopeptidases/metabolismo
4.
Int J Mol Sci ; 22(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34575833

RESUMO

Arterial hypertension (AH) is a major risk factor for the development of cardiovascular diseases. It is estimated that the disease affects between 10% and 20% of the adult population and is responsible for 5.8% of all deaths worldwide. Several pathophysiologic factors are crucial in AH, including inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress and inflammation. The heart, kidney, brain, retina and arterial blood vessels are prime targets of hypertensive damage. Uncontrolled and untreated AH accelerates the damage to these organs and could cause their failure. Damage to these organs could also manifest as coronary heart disease, cognitive impairment, retinopathy or optic neuropathy. For better understanding, it is important to analyze molecular factors which take part in pathogenesis of AH and hypertension-related target organ damage. In our paper, we would like to focus on molecular interactions of AH in the heart, blood vessels, brain and kidneys. We focus on matrix metalloproteinases, the role of immune system, the renin-angiotensin-aldosterone system and oxidative stress in hypertensive induced organ damage.


Assuntos
Pressão Arterial , Artérias/fisiopatologia , Suscetibilidade a Doenças , Hipertensão/etiologia , Hipertensão/fisiopatologia , Angiotensina II/metabolismo , Animais , Biomarcadores , Estresse do Retículo Endoplasmático , Humanos , Hipertensão/patologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Metaloproteinases da Matriz/metabolismo , Especificidade de Órgãos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Renina/metabolismo , Remodelação Vascular
5.
Cells ; 10(9)2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34572026

RESUMO

Adrenal steroid hormone production is a dynamic process stimulated by adrenocorticotropic hormone (ACTH) and angiotensin II (AngII). These ligands initialize a rapid and robust gene expression response required for steroidogenesis. Here, we compare the predominant human immortalized cell line model, H295R cell, with primary cultures of adult adrenocortical cells derived from human kidney donors. We performed temporally resolved RNA-seq on primary cells stimulated with either ACTH or AngII at multiple time points. The magnitude of the expression dynamics elicited by ACTH was greater than AngII in primary cells. This is likely due to the larger population of adrenocortical cells that are responsive to ACTH. The dynamics of stimulus-induced expression in H295R cells are mostly recapitulated in primary cells. However, there are some expression responses in primary cells absent in H295R cells. These data are a resource for the endocrine community and will help researchers determine whether H295R is an appropriate model for the specific aspect of steroidogenesis that they are studying.


Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Aldosterona/metabolismo , Transcriptoma/efeitos dos fármacos , Angiotensina II/metabolismo , Células Cultivadas , Humanos , Hidrocortisona/metabolismo
6.
Biomolecules ; 11(7)2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34356603

RESUMO

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.


Assuntos
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/análogos & derivados , Animais , COVID-19/metabolismo , Cristalografia por Raios X , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Modelos Moleculares , Coelhos , Receptor Tipo 1 de Angiotensina/química , Vasoconstrição/efeitos dos fármacos
7.
Arch Biochem Biophys ; 711: 109021, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34464591

RESUMO

BACKGROUND: Apelin and its receptor angiotensin receptor - like 1 (APJ) are closely related to renal fibrosis, but their specific roles in renal fibrosis are still controversial. In this article, we discussed the role of Apelin/APJ system in renal fibrosis and its mechanism. METHODS: Chronic intermittent hypoxia (CIH) rat model was established to induce the environment of renal fibrosis and a competitive antagonist of the APJ receptor ML221 was administered to CIH rats. The rats were divided into Control, CIH and ML221 groups. HE staining was used to detect the inflammatory injury and fibrosis of renal tissue. The expressions of renal fibrosis-related indicators transforming growth factor-ß (TGF-ß), α-smooth muscle actin (α-SMA) and Human type I collagen (Col-Ⅰ) were detected by immunohistochemistry. The levels of oxidative stress indexes reactive oxygen species (ROS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) and inflammation-related indexes Interleukin (IL) -6, tumor necrosis factor-α (TNF-α) and IL-1ß were detected by ELISA. At the same time, the levels of Apelin-13 and AngiotensinII (AngⅡ) were also measured by ELISA. Finally, western blot was used to detect the expression of Apelin pathway and renal fibrosis-related proteins. In addition, at the cellular level, we divided the cells into Control, CIH, Apelin-13 and Apelin-13+ML-221 groups to further verify the specific mechanisms at the cellular level. RESULTS: The expression of Apeline-13 and its related pathways was significantly increased after the induction of CIH in rats. However, the degree of renal fibrosis in ML221 group was further significantly increased after inhibiting the expression of Apelin. At the cellular level, CIH model cells treated with Apelin-13 significantly reduced cell proliferation, oxidative stress and inflammatory response, and decreased the expression of fibrosis-related proteins, which can be reversed by ML221 administration. CONCLUSION: The increased reactivity of Apelin may be one of the protective mechanisms against renal fibrosis induced by CIH.


Assuntos
Apelina/metabolismo , Fibrose/metabolismo , Hipóxia/complicações , Nefropatias/metabolismo , Angiotensina II/metabolismo , Animais , Receptores de Apelina/antagonistas & inibidores , Linhagem Celular , Fibrose/etiologia , Fibrose/patologia , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Nitrobenzoatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Piranos/farmacologia , Ratos Wistar
8.
Biochem Pharmacol ; 192: 114738, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418354

RESUMO

The renin-angiotensin system, with the octapeptide angiotensin II as key player, is important in the renal, cardiac and vascular physiology. Prolyl carboxypeptidase (PRCP), prolyl endopeptidase (PREP) and angiotensin converting enzyme 2 (ACE2) are reported to be involved in the conversion of angiotensin II to angiotensin (1-7). Previous investigations showed that the processing of angiotensin II is cell- and species-specific and little is known about its conversion in human endothelial cells. Therefore, we aimed to investigate the C-terminal processing of angiotensin II and III in comparison to the processing of des-Arg9-bradykinin in human endothelial cells. To this end, human umbilical vein and aortic endothelial cells (HUVEC and HAoEC) were incubated with the peptides for different time periods. Mass spectrometry analysis was performed on the supernatants to check for cleavage products. Contribution of PRCP, ACE2 and PREP to the peptide cleavage was evaluated by use of the selective inhibitors compound 8o, DX600 and KYP-2047. The use of these selective inhibitors revealed that the C-terminal cleavage of angiotensin II and III was PRCP-dependent in HUVEC and HAoEC. In contrast, the C-terminal cleavage of des-Arg9-bradykinin was PRCP-dependent in HUVEC and PRCP- and ACE2-dependent in HAoEC. With this study, we contribute to a better understanding of the processing of peptides involved in the alternative renin-angiotensin system. We conclude that PRCP is the main enzyme for the C-terminal processing of angiotensin peptides in human umbilical vein and aortic endothelial cells. For the first time the contribution of PRCP was investigated by use of a selective PRCP-inhibitor.


Assuntos
Angiotensina III/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Aorta/metabolismo , Carboxipeptidases/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Angiotensina III/antagonistas & inibidores , Aorta/citologia , Aorta/efeitos dos fármacos , Carboxipeptidases/antagonistas & inibidores , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Peptídeos/farmacologia
9.
Sci Rep ; 11(1): 16525, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400742

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-ß and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-ß induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-ß and angiotensin II synergistically induced TGF-ß, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.


Assuntos
Ergocalciferóis/uso terapêutico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Vitamina D/uso terapêutico , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensinogênio/metabolismo , Animais , Bleomicina , Modelos Animais de Doenças , Ergocalciferóis/farmacologia , Losartan/farmacologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Vitamina D/farmacologia
11.
Clin Sci (Lond) ; 135(14): 1727-1731, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34291792

RESUMO

Although the existence of a brain renin-angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason for this is the virtual lack of renin at brain tissue sites. Moreover, although renin's substrate, angiotensinogen, appears to be synthesized locally in the brain, brain angiotensin (Ang) II disappeared after selective silencing of hepatic angiotensinogen. This implies that brain Ang generation depends on hepatic angiotensinogen after all. Rodrigues et al. (Clin Sci (Lond) (2021) 135:1353-1367) generated a transgenic mouse model overexpressing full-length rat angiotensinogen in astrocytes, and observed massively elevated brain Ang II levels, increased sympathetic nervous activity and vasopressin, and up-regulated erythropoiesis. Yet, blood pressure and kidney function remained unaltered, and surprisingly no other Ang metabolites occurred in the brain. Circulating renin was suppressed. This commentary critically discusses these findings, concluding that apparently in the brain, overexpressed angiotensinogen can be cleaved by an unidentified non-renin enzyme, yielding Ang II directly, which then binds to Ang receptors, allowing no metabolism by angiotensinases like ACE2 and aminopeptidase A. Future studies should now unravel the identity of this non-renin enzyme, and determine whether it also contributes to Ang II generation at brain tissue sites in wildtype animals. Such studies should also re-evaluate the concept that Ang-(1-7) and Ang III, generated by ACE2 and aminopeptidase A, respectively, have important functions in the brain.


Assuntos
Encéfalo/metabolismo , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Renina/metabolismo , Angiotensina II/metabolismo , Humanos , Hipertensão/metabolismo , Receptores de Angiotensina/metabolismo
12.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281199

RESUMO

The current global prevalence of heart failure is estimated at 64.34 million cases, and it is expected to increase in the coming years, especially in countries with a medium-low sociodemographic index where the prevalence of risk factors is increasing alarmingly. Heart failure is associated with many comorbidities and among them, cancer has stood out as a contributor of death in these patients. This connection points out new challenges both in the context of the pathophysiological mechanisms involved, as well as in the quality of life of affected individuals. A hallmark of heart failure is chronic activation of the renin-angiotensin-aldosterone system, especially marked by a systemic increase in levels of angiotensin-II, a peptide with pleiotropic activities. Drugs that target the renin-angiotensin-aldosterone system have shown promising results both in the prevention of secondary cardiovascular events in myocardial infarction and heart failure, including a lower risk of certain cancers in these patients, as well as in current cancer therapies; therefore, understanding the mechanisms involved in this complex relationship will provide tools for a better diagnosis and treatment and to improve the prognosis and quality of life of people suffering from these two deadly diseases.


Assuntos
Isquemia Miocárdica/fisiopatologia , Neoplasias/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/metabolismo , Neoplasias/metabolismo , Renina/metabolismo
13.
Biochim Biophys Acta Gen Subj ; 1865(9): 129950, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34144121

RESUMO

BACKGROUND: Tubule-interstitial injury (TII) is one of the mechanisms involved in the progression of renal diseases with progressive proteinuria. Angiotensin II (Ang II) type 1 receptor blockers (ARBs) have been successfully used to treat renal diseases. However, the mechanism correlating treatment with ARBs and proteinuria is not completely understood. The hypothesis that the anti-proteinuric effect of losartan is associated with the modulation of albumin endocytosis in PT epithelial cells (PTECs) was assessed. METHODS: We used a subclinical acute kidney injury animal model (subAKI) and LLC-PK1 cells, a model of PTECs. RESULTS: In subAKI, PT albumin overload induced TII development, measured by: (1) increase in urinary lactate dehydrogenase and γ-glutamyltranspeptidase activity; (2) proteinuria associated with impairment in megalin-mediated albumin reabsorption; (3) increase in luminal and interstitial space in tubular cortical segments. These effects were avoided by treating the animals with losartan, an ARB. Using LLC-PK1 cells, we observed that: (1) 20 mg/mL albumin increased the secretion of Ang II and decreased megalin-mediated albumin endocytosis; (2) the effects of Ang II and albumin were abolished by 10-8 M losartan; (3) MEK/ERK pathway is the molecular mechanism underlying the Ang II-mediated inhibitory effect of albumin on PT albumin endocytosis. CONCLUSION: Our results show that PT megalin-mediated albumin endocytosis is a possible target during the treatment of renal diseases patients with ARB. GENERAL SIGNIFICANCE: The findings obtained in the present work represents a step forward to the current knowledge on about the role of ARBs in the treatment of renal disease.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Albuminas/antagonistas & inibidores , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Losartan/farmacologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Injúria Renal Aguda/metabolismo , Albuminas/metabolismo , Angiotensina II/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
14.
Curr Hypertens Rep ; 23(6): 34, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34110521

RESUMO

PURPOSE OF REVIEW: The sodium (Na+) and hydrogen (H+) exchanger 3 (NHE3), known as solute carrier family 9 member 3 (SLC9A3), mediates active transcellular Na+ and bicarbonate reabsorption in the small intestine of the gut and proximal tubules of the kidney. The purpose of this article is to review and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure (BP) homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension. RECENT FINDINGS: Recently, our and other laboratories have generated or used novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal BP homeostasis and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The new findings demonstrate that NHE3 contributes to about 10 to 15 mmHg to basal blood pressure levels, and that deletion of NHE3 at the whole-kidney or proximal tubule level, or pharmacological inhibition of NHE3 at the kidney level with an orally absorbable NHE3 inhibitor AVE-0657, attenuates ~ 50% of Ang II-induced hypertension in mice. The results support the proof-of-concept hypothesis that NHE3 plays critical roles in physiologically maintaining normal BP and in the development of Ang II-dependent hypertension. Our results also strongly suggest that NHE3 in the proximal tubules of the kidney may be therapeutically targeted to treat poorly controlled hypertension in humans.


Assuntos
Hipertensão , Angiotensina II/metabolismo , Animais , Humanos , Hipertensão/tratamento farmacológico , Túbulos Renais Proximais , Camundongos , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio
15.
Front Immunol ; 12: 649122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177896

RESUMO

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.


Assuntos
Transtornos da Coagulação Sanguínea/metabolismo , COVID-19/metabolismo , SARS-CoV-2/fisiologia , Angiotensina II/metabolismo , Animais , Transtornos da Coagulação Sanguínea/imunologia , COVID-19/imunologia , Citocinas/metabolismo , Fator XIIa/metabolismo , Humanos , Inflamação , Mediadores da Inflamação/metabolismo
16.
Infez Med ; 29(2): 167-180, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34061781

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), in a very short span of thirteen months has taken a considerable toll on humanity, resulting in over 3 million deaths with more than 150 million confirmed cases as on May 1, 2021. In the scarcity of a potential antiviral and protective vaccine, COVID-19 has posed high public health concerns, panic, and challenges to limit the spread of this pandemic virus. Only recently have a few vaccine candidates been developed, and vaccination programs have started in some countries. Multiple clinical presentations of COVID-19, animal spillover, cross-species jumping, zoonotic concerns, and emergence of virus variants have altogether created havoc during this ongoing pandemic. Several bodies of research are continuously working to elucidate the exact molecular mechanisms of the pathogenesis. To develop a prospective antiviral therapy/vaccine for SARSCoV-2, it is quite essential to gain insight into the immunobiology and molecular virology of SARS-CoV-2. A thorough literature search was conducted up to 28th February 2021 in the PubMed and other databases for the articles describing the immunopathology and immune response of SARS-CoV-2 infection, which were critically evaluated and used to compile this article to present an overall update. Some of the information was drawn from studies on previous MERS and SARS viruses. Innate as well as adaptive immunity responses are elicited by exposure to SARS-CoV-2. SARS-CoV-2 establishes a successful infection by escaping the host immunity as well as over activating the innate immune mechanisms that result in severe disease outcomes, including cytokine storm. This review summarizes the immunopathology and molecular immune mechanisms elicited during SARS-CoV-2 infection, and their similarities with MERS-CoV and SARS-CoV.


Assuntos
Imunidade Adaptativa , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Facilitadores/imunologia , Linfócitos B/imunologia , COVID-19/virologia , Humanos , Imunidade Celular , Pulmão/enzimologia , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/imunologia , Ligação Viral
17.
Eur J Pharmacol ; 905: 174184, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34004211

RESUMO

Autophagy is essential to vessel homeostasis and function in the cardiovascular system. Ligustilide (LIG) is one of the main active ingredients extracted from traditional Chinese medicines, such as Ligusticum chuanxiong, Angelica, and other umbelliferous plants, and reported to have cardiovascular protective effects. In this study, we explore the effects and the potential mechanism of ligustilide on the Ang II-induced autophagy in A7r5 cells. Our results showed that ligustilide inhibited the Ang II-induced autophagy in A7r5 cells and down regulated the expression of autophagy-related proteins LC3, ULK1, and Beclin-1. Ligustilide exerted a protective effect on the reduction of the concentrations of reactive oxygen species and Ca2+ and upregulated the nitric oxide concentration in A7r5 cells with Ang II-induced autophagy. Additionally, the analyses of network pharmacological targets and potential signal pathways indicated that the target of ligustilide to regulate autophagy was related to the Akt/mTOR signaling pathway. Furthermore, ligustilide could upregulate the expression of p-Akt and p-mTOR and inhibit the expression of LC3II in A7r5 cells with Ang II-induced autophagy. These findings showed that ligustilide inhibited the autophagic flux in A7r5 cells induced by Ang II via the activation of the Akt/mTOR signaling pathway.


Assuntos
4-Butirolactona/análogos & derivados , Angiotensina II/metabolismo , Autofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , 4-Butirolactona/farmacologia , Angiotensina II/toxicidade , Animais , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Mapas de Interação de Proteínas , Ratos , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
Clin Sci (Lond) ; 135(10): 1295-1309, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33978148

RESUMO

OBJECTIVE: Aortic macrophage accumulation is characteristic of the pathogenesis of abdominal aortic aneurysm (AAA) but the mechanisms of macrophage accumulation and their phenotype are poorly understood. Lymphatic vessel endothelial receptor-1 (Lyve-1+) resident aortic macrophages independently self-renew and are functionally distinct from monocyte-derived macrophages recruited during inflammation. We hypothesized that Lyve-1+ and Lyve-1- macrophages differentially contribute to aortic aneurysm. Approach and results: Angiotensin-2 and ß-aminopropionitrile (AT2/BAPN) were administered to induce AAA in C57BL/6J mice. Using immunohistochemistry (IHC), we demonstrated primarily adventitial accumulation of aortic macrophages, and in association with areas of elastin fragmentation and aortic dissection. Compared with controls, AAA was associated with a relative percent depletion of Lyve-1+ resident aortic macrophages and accumulation of Lyve-1- macrophages. Using CD45.1/CD45.2 parabiosis, we demonstrated aortic macrophage recruitment in AAA. Depletion of aortic macrophages in CCR2-/- mice was associated with reduced aortic dilatation indicating the functional role of recruitment from the bone marrow. Depletion of aortic macrophages using anti-macrophage colony-stimulating factor 1 receptor (MCSF1R)-neutralizing antibody (Ab) reduced the incidence of AAA. Conditional depletion of Lyve-1+ aortic macrophages was achieved by generating Lyve-1wt/cre Csf1rfl/fl mice. Selective depletion of Lyve-1+ aortic macrophages had no protective effects following AT2/BAPN administration and resulted in increased aortic dilatation in the suprarenal aorta. CONCLUSIONS: Aortic macrophage accumulation in AAA derives from adventitial recruitment of Lyve-1- macrophages, with relative percent depletion of Lyve-1+ macrophages. Selective targeting of macrophage subtypes represents a potential novel therapeutic avenue for the medical treatment of AAA.


Assuntos
Angiotensina II/metabolismo , Aorta Abdominal/metabolismo , Macrófagos/imunologia , Proteínas de Membrana Transportadoras/metabolismo , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma Aórtico/patologia , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Inflamação/patologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana Transportadoras/imunologia , Camundongos , Transdução de Sinais/imunologia
19.
Clin Sci (Lond) ; 135(11): 1353-1367, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34013320

RESUMO

In spite of the fact that the modulatory effects of angiotensin II (Ang II) on the sympathetic nerve activity to targeted organs involved in blood pressure (BP) regulation is well acknowledged, the local production of this peptide in the brain and the consequences of enhanced central Ang II beyond the cardiovascular system are not yet well comprehended. In the present study, we generated and validated a new transgenic mouse line overexpressing the rat full-length angiotensinogen (Agt) protein specifically in the brain (Agt-Tg). Adult Agt-Tg mice presented overall increased gene expression of total Agt in the brain including brainstem and hypothalamus. In addition, the excess of Agt led to abundantly detectable brain Ang II levels as well as increased circulating copeptin levels. Agt-Tg displayed raised BP in acute recordings, while long-term telemetrically measured basal BP was indistinguishable from wild-types. Agt-Tg has altered peripheral renin-angiotensin system and vasomotor sympathetic tone homeostasis because renal gene expression analysis, plasma Ang II measurements and ganglionic blockade experiments revealed suppressed renin expression and reduced Ang II and higher neurogenic pressure response, respectively. Plasma and urine screens revealed apparently normal fluid and electrolyte handling in Agt-Tg. Interestingly, hematological analyses showed increased hematocrit in Agt-Tg caused by enhanced erythropoiesis, which was reverted by submitting the transgenic mice to a long-term peripheral sympathectomy protocol. Collectively, our findings suggest that Agt-Tg is a valuable tool to study not only brain Ang II formation and its modulatory effects on cardiovascular homeostasis but also its role in erythropoiesis control via autonomic modulation.


Assuntos
Angiotensina II/metabolismo , Eritropoese/fisiologia , Homeostase/fisiologia , Sistema Renina-Angiotensina/fisiologia , Animais , Encéfalo/metabolismo , Hipertensão/metabolismo , Rim/metabolismo , Camundongos , Camundongos Transgênicos , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/metabolismo
20.
Kidney Blood Press Res ; 46(3): 331-341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34034251

RESUMO

BACKGROUND: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). METHODS: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. RESULTS: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. CONCLUSION: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Tetrazóis/farmacologia , Angiotensina II/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Denervação , Taxa de Filtração Glomerular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/fisiologia , Masculino , Ratos Sprague-Dawley , Sódio/metabolismo , Água/metabolismo
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