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1.
Front Endocrinol (Lausanne) ; 12: 725967, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34745001

RESUMO

The renin-angiotensin system (RAS) is crucially involved in the physiology and pathology of all organs in mammals. Angiotensin-converting enzyme 2 (ACE2), which is a homolog of ACE, acts as a negative regulator in the homeostasis of RAS. ACE2 has been proven to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic. As SARS-CoV-2 enters the host cells through binding of viral spike protein with ACE2 in humans, the distribution and expression level of ACE2 may be critical for SARS-CoV-2 infection. Growing evidence shows the implication of ACE2 in pathological progression in tissue injury and several chronic conditions such as hypertension, diabetes, and cardiovascular disease; this suggests that ACE2 is essential in the progression and clinical prognosis of COVID-19 as well. Therefore, we summarized the expression and activity of ACE2 under various conditions and regulators. We further discussed its potential implication in susceptibility to COVID-19 and its potential for being a therapeutic target in COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/prevenção & controle , Peptidil Dipeptidase A/fisiologia , Sistema Renina-Angiotensina/fisiologia , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Humanos , Terapia de Alvo Molecular , Pandemias , SARS-CoV-2
2.
Medicine (Baltimore) ; 100(41): e27496, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731131

RESUMO

ABSTRACT: Using animal models and molecular biology researches, hyperuricemia has been shown to instruct renal arteriolopathy, arterial hypertension, and microvascular injury involving the renin-angiotensin system and resulting in renal function impairment. Nevertheless, the association between uric acid levels and the development of albuminuria has been under-investigated in patients with type 2 diabetes mellitus. Patients with type 2 diabetes and regular outpatient visits were recruited from the Puli Branch of the Taichung Veterans General Hospital in Taiwan since January 2014. Demographics, lifestyle features, and medical history were gathered by well-trained interviewers. All participants underwent comprehensive physical examinations, including a biochemical assay of venous blood specimens and urine samples after an 8-hour overnight fast. Participants were followed until June 2018. The primary outcome was the albuminuria incidence. Univariable and multivariable Cox regression analysis were employed to explore the relation between uric acid and incident albuminuria. Uric acid cutoffs for incident albuminuria were determined with the receiver operator characteristic curve. We included 247 qualified subjects (mean age: 64.78 years old [standard deviation = 11.29 years]; 138 [55.87%] men). During a 4.5-year follow-up duration, 20 subjects with incident albuminuria were recognized. Serum uric acid was significantly associated with an increased risk of incident albuminuria (adjusted hazard ratio = 2.39; 95% confidence interval: 1.53-3.75; P < .001) with potential confounders adjustment. The uric acid cutoff point was 6.9 mg/dL (area under the curve 0.708, sensitivity 60.0%, specificity 84.58%) for incident albuminuria. Serum uric acid was associated with incident albuminuria among patients with type 2 diabetes.


Assuntos
Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Ácido Úrico/sangue , Idoso , Albuminúria/etiologia , Animais , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Feminino , Humanos , Hipertensão/complicações , Hiperuricemia/complicações , Incidência , Masculino , Camundongos , Microvasos/lesões , Pessoa de Meia-Idade , Modelos Animais , Insuficiência Renal/etiologia , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Taiwan/epidemiologia
3.
Int J Mol Sci ; 22(21)2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34769350

RESUMO

The 2019 novel coronavirus, known as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19), is causing a global pandemic. The virus primarily affects the upper and lower respiratory tracts and raises the risk of a variety of non-pulmonary consequences, the most severe and possibly fatal of which are cardiovascular problems. Data show that almost one-third of the patients with a moderate or severe form of COVID-19 had preexisting cardiovascular comorbidities such as diabetes mellitus, obesity, hypertension, heart failure, or coronary artery disease. SARS-CoV2 causes hyper inflammation, hypoxia, apoptosis, and a renin-angiotensin system imbalance in a variety of cell types, primarily endothelial cells. Profound endothelial dysfunction associated with COVID-19 can be the cause of impaired organ perfusion that may generate acute myocardial injury, renal failure, and a procoagulant state resulting in thromboembolic events. We discuss the most recent results on the involvement of endothelial dysfunction in the pathogenesis of COVID-19 in patients with cardiometabolic diseases in this review. We also provide insights on treatments that may reduce the severity of this viral infection.


Assuntos
COVID-19/patologia , Células Endoteliais/metabolismo , COVID-19/complicações , COVID-19/virologia , Síndrome da Liberação de Citocina/etiologia , Células Endoteliais/citologia , Células Endoteliais/virologia , Insuficiência Cardíaca/etiologia , Humanos , Insuficiência Renal/etiologia , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2/isolamento & purificação , Trombose/etiologia
4.
Med Clin North Am ; 105(6): 1065-1080, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34688415

RESUMO

Hyperaldosteronism is a relatively more common disorder than previously recognized. Patients with hyperaldosteronism are at high risk for cardiovascular events. Patients suspected of having hyperaldosteronism should undergo initial screening and subsequent confirmatory testing to establish a biochemical diagnosis. Although adrenal computed tomography/magnetic resonance imaging scans often define a disease's subtype, adrenal vein sampling, in order to determine lateralization, may be necessary in some patients who are surgical candidates. Medical therapy using optimal doses of mineralocorticoid receptor antagonists can control symptoms and normalize plasma renin activity. The long-term outcome of patients treated with either surgical or optimal medical therapy appears similar.


Assuntos
Aldosterona/metabolismo , Hiperaldosteronismo/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Aldosterona/sangue , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirurgia , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia
5.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360741

RESUMO

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Obesidade/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Dieta , Humanos , Sistema Renina-Angiotensina/fisiologia , Índice de Gravidade de Doença
6.
Pharmazie ; 76(8): 342-350, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412732

RESUMO

Angiotensin-2 converting enzyme (ACE2), a key element of the renin-angiotensin-system (RAS), is not only the direct target of infection by the human SARS-Cov-2 virus but is at the same the root for the complex pathogenetic events of COVID-19. From a pharmaceutical perspective, several established classes of medicines are involved in different phases of the disease. From their known mechanisms of action, a comprehensive understanding of COVID-19 will be hopefully soon delineated. A set of proven medicines is available to cope at least with some of the pathologies involved. To arrive back to normal life, vaccinations and broad consideration of hygienic measures are to be complemented by effective medicines to treat airborne viral infections. Therapeutic schemes based on a comprehensive understanding of the disease will include drug combinations made up from both established drugs as well as novel drugs presently under development.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , Sistema Renina-Angiotensina/fisiologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Desenvolvimento de Medicamentos , Humanos , SARS-CoV-2/efeitos dos fármacos
7.
Biomolecules ; 11(7)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34356659

RESUMO

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in women worldwide. Its social impact in the case of premature CAD is particularly devastating. Many differences in the presentation of the disease in women as compared to men, including atypical symptoms, microvascular involvement, and differences in pathology of plaque formation or progression, make CAD diagnosis in women a challenge. The contribution of different risk factors, such as smoking, diabetes, hyperlipidemia, or obesity, may vary between women and men. Certain pathological pathways may have different sex-related magnitudes on CAD formation and progression. In spite of the already known differences, we lack sufficiently powered studies, both clinical and experimental, that assess the multipathogenic differences in CAD formation and progression related to sex in different age periods. A growing quantity of data that are presented in this article suggest that thrombosis with fibrinogen is of more concern in the case of premature CAD in women than are other coagulation factors, such as factors VII and VIII, tissue-type plasminogen activator, and plasminogen inhibitor-1. The rise in fibrinogen levels in inflammation is mainly affected by interleukin-6 (IL-6). The renin-angiotensin (RA) system affects the inflammatory process by increasing the IL-6 level. Unlike in men, in young women, the hypertensive arm of the RA system is naturally downregulated by estrogens. At the same time, estrogens promote the fibrinolytic path of the RA system. In young women, the promoted fibrinolytic process upregulates IL-6 release from leukocytes via fibrin degradation products. Moreover, fibrinogen, whose higher levels are observed in women, increases IL-6 synthesis and exacerbates inflammation, contributing to CAD. Therefore, the synergistic interplay between thrombosis, inflammation, and the RA system appears to have a more significant influence on the underlying CAD atherosclerotic plaque formation in young women than in men. This issue is further discussed in this review. Fibrinogen is the biomolecule that is central to these three pathways. In this review, fibrinogen is shown as the biomolecule that possesses a different impact on CAD formation, progression, and destabilization in women to that observed in men, being more pathogenic in women at the early stages of the disease than in men. Fibrinogen is a three-chain glycoprotein involved in thrombosis. Although the role of thrombosis is of great magnitude in acute coronary events, fibrinogen also induces atherosclerosis formation by accumulating in the arterial wall and enabling low-density lipoprotein cholesterol aggregation. Its level rises during inflammation and is associated with most cardiovascular risk factors, particularly smoking and diabetes. It was noted that fibrinogen levels were higher in women than in men as well as in the case of premature CAD in women. The causes of this phenomenon are not well understood. The higher fibrinogen levels were found to be associated with a greater extent of coronary atherosclerosis in women with CAD but not in men. Moreover, the lysability of a fibrin clot, which is dependent on fibrinogen properties, was reduced in women with subclinical CAD compared to men at the same stage of the disease, as well as in comparison to women without coronary artery atherosclerosis. These findings suggest that the magnitude of the pathological pathways contributing to premature CAD differs in women and men, and they are discussed in this review. While many gaps in both experimental and clinical studies on sex-related differences in premature CAD exist, further studies on pathological pathways are needed.


Assuntos
Doença da Artéria Coronariana/etiologia , Fibrinogênio/metabolismo , Inflamação/complicações , Sistema Renina-Angiotensina/fisiologia , Trombose/complicações , Aterosclerose/etiologia , Doença da Artéria Coronariana/sangue , Estrogênios/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Masculino , Fatores Sexuais , Fumar
8.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445698

RESUMO

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Neprilisina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/metabolismo , Anti-Hipertensivos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Peptídeos Natriuréticos/metabolismo , Peptídeos Natriuréticos/fisiologia , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologia , Tetrazóis/farmacologia
9.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34351870

RESUMO

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.


Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças de Pequenos Vasos Cerebrais/tratamento farmacológico , Doenças de Pequenos Vasos Cerebrais/etiologia , Hiperemia/tratamento farmacológico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Anlodipino/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Demência Vascular/tratamento farmacológico , Demência Vascular/etiologia , Demência Vascular/fisiopatologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eplerenona/administração & dosagem , Eplerenona/uso terapêutico , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperemia/fisiopatologia , Losartan/administração & dosagem , Losartan/uso terapêutico , Masculino , Camundongos , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
10.
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
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.
Biochem Pharmacol ; 192: 114673, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252409

RESUMO

The AT1 receptor, a major effector of the renin-angiotensin system, has been extensively studied in the context of cardiovascular and renal disease. Moreover, angiotensin receptor blockers, sartans, are among the most frequently prescribed drugs for the treatment of hypertension, chronic heart failure and chronic kidney disease. However, precise molecular insights into the structure of this important drug target have not been available until recently. In this context, seminal studies have now revealed exciting new insights into the structure and biased signaling of the receptor and may thus foster the development of novel therapeutic approaches to enhance the efficacy of pharmacological angiotensin receptor antagonism or to enable therapeutic induction of biased receptor activity. In this review, we will therefore highlight these and other seminal publications to summarize the current understanding of the tertiary structure, ligand binding properties and downstream signal transduction of the AT1 receptor.


Assuntos
Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 1 de Angiotensina/química , Angiotensina II/biossíntese , Angiotensina II/química , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Animais , Expressão Gênica , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Estrutura Secundária de Proteína , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
13.
Physiol Rep ; 9(11): e14800, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34121359

RESUMO

The objective of this review is to give an overview of the pathophysiological effects of the Coronavirus Disease 2019 (COVID-19) in relation to hypertension (HT), with a focus on the Renin-Angiotensin-Aldosterone System (RAAS) and the MAS receptor. HT is a multifactorial disease and a public health burden, as it is a risk factor for diseases like stroke, coronary artery disease, and heart failure, leading to 10.4 million deaths yearly. Blood pressure is regulated by the RAAS. The system consists of two counter-regulatory axes: ACE/ANG-II/AT1 R and ACE2/ANG-(1-7)/MAS. The main regulatory protein in balancing the RAAS is angiotensin-converting enzyme 2 (ACE2). The protein also functions as the main mediator of endocytosis of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. SARS-CoV-2 is the cause of COVID-19 and has caused a worldwide pandemic; however, the treatment and prophylaxis of COVID-19 are limited. Several drugs and vaccines are currently being tested in clinical trials with a few already approved by EMA and FDA. HT is a major risk factor regarding the severity and fatality of COVID-19, and the RAAS plays an important role in COVID-19 infection since SARS-CoV-2 can lead to a dysregulation of the system by reducing the ACE2 expression. The exact mechanisms of HT in relation to COVID-19 remain uncertain, and more research is needed for further elucidation.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , COVID-19/fisiopatologia , Hipertensão/virologia , Sistema Renina-Angiotensina/fisiologia , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Hipertensão/fisiopatologia , Pandemias , Fatores de Risco , SARS-CoV-2/isolamento & purificação
14.
Physiology (Bethesda) ; 36(4): 220-234, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34159807

RESUMO

Much excitement exists over the cardioprotective and life-extending effects of caloric restriction (CR). This review integrates population studies with experimental animal research to address the positive and negative impact of mild and severe CR on cardiovascular physiology and pathophysiology, with a particular focus on the renin-angiotensin system (RAS). We also highlight the gaps in knowledge and areas ripe for future physiological research.


Assuntos
Pressão Sanguínea/fisiologia , Restrição Calórica , Fenômenos Fisiológicos Cardiovasculares , Sistema Renina-Angiotensina/fisiologia , Animais , Sistema Cardiovascular/metabolismo , Humanos
15.
OMICS ; 25(7): 408-416, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34191617

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.


Assuntos
Neprilisina/química , Bradicinina/genética , Bradicinina/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , SARS-CoV-2
16.
Int J Mol Sci ; 22(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065735

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is still an ongoing global health crisis. Immediately after the inhalation of SARS-CoV-2 viral particles, alveolar type II epithelial cells harbor and initiate local innate immunity. These particles can infect circulating macrophages, which then present the coronavirus antigens to T cells. Subsequently, the activation and differentiation of various types of T cells, as well as uncontrollable cytokine release (also known as cytokine storms), result in tissue destruction and amplification of the immune response. Vitamin D enhances the innate immunity required for combating COVID-19 by activating toll-like receptor 2. It also enhances antimicrobial peptide synthesis, such as through the promotion of the expression and secretion of cathelicidin and ß-defensin; promotes autophagy through autophagosome formation; and increases the synthesis of lysosomal degradation enzymes within macrophages. Regarding adaptive immunity, vitamin D enhances CD4+ T cells, suppresses T helper 17 cells, and promotes the production of virus-specific antibodies by activating T cell-dependent B cells. Moreover, vitamin D attenuates the release of pro-inflammatory cytokines by CD4+ T cells through nuclear factor κB signaling, thereby inhibiting the development of a cytokine storm. SARS-CoV-2 enters cells after its spike proteins are bound to angiotensin-converting enzyme 2 (ACE2) receptors. Vitamin D increases the bioavailability and expression of ACE2, which may be responsible for trapping and inactivating the virus. Activation of the renin-angiotensin-aldosterone system (RAS) is responsible for tissue destruction, inflammation, and organ failure related to SARS-CoV-2. Vitamin D inhibits renin expression and serves as a negative RAS regulator. In conclusion, vitamin D defends the body against SARS-CoV-2 through a novel complex mechanism that operates through interactions between the activation of both innate and adaptive immunity, ACE2 expression, and inhibition of the RAS system. Multiple observation studies have shown that serum concentrations of 25 hydroxyvitamin D are inversely correlated with the incidence or severity of COVID-19. The evidence gathered thus far, generally meets Hill's causality criteria in a biological system, although experimental verification is not sufficient. We speculated that adequate vitamin D supplementation may be essential for mitigating the progression and severity of COVID-19. Future studies are warranted to determine the dosage and effectiveness of vitamin D supplementation among different populations of individuals with COVID-19.


Assuntos
Imunidade Adaptativa , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Vitamina D/metabolismo , Vitamina D/farmacologia , COVID-19/mortalidade , COVID-19/fisiopatologia , COVID-19/virologia , Síndrome da Liberação de Citocina/complicações , Citocinas/metabolismo , Humanos , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/fisiologia
17.
Int J Biol Sci ; 17(8): 1925-1939, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34131396

RESUMO

Background: Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) allow entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells and play essential roles in cancer therapy. However, the functions of ACE2 and TMPRSS2 in kidney cancer remain unclear, especially as kidneys are targets for SARS-CoV-2 infection. Methods: UCSC Xena project, the Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases (GSE30589 and GSE59185) were searched for gene expression in human tissues, gene expression data, and clinical information. Several bioinformatics methods were utilized to analyze the correlation between ACE2 and TMPRSS2 with respect to the prognosis of kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP). Results: ACE2 expression was significantly upregulated in tumor tissue, while its downregulation was associated with low survival in KIRC and KIRP patients. TMPRSS2 was downregulated in KIRC and KIRP, and its expression was not correlated with patient survival. According to clinical risk factor-based prediction models, ACE2 exhibits predictive accuracy for kidney cancer prognosis and is correlated with metabolism and immune infiltration. In an animal model, ACE2 expression was remarkably downregulated in SARS-CoV-2-infected cells compared to in the control. Conclusion: ACE2 expression is highly correlated with various metabolic pathways and is involved in immune infiltration.it plays a crucial role than TMPRSS2 in diagnosing and prognosis of kidney cancer patients. The overlap in ACE2 expression between kidney cancer and SARS-CoV-2 infection suggests that patients with KIRC or KIRP are at high risk of developing serious symptoms.


Assuntos
Enzima de Conversão de Angiotensina 2/biossíntese , COVID-19/complicações , Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Receptores Virais/biossíntese , SARS-CoV-2 , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Chlorocebus aethiops , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Animais , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Especificidade de Órgãos , Prognóstico , Modelos de Riscos Proporcionais , Receptores Virais/genética , Sistema Renina-Angiotensina/fisiologia , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética , Serina Endopeptidases/fisiologia , Análise Serial de Tecidos , Células Vero
19.
Lancet Respir Med ; 9(8): 863-872, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34126053

RESUMO

BACKGROUND: SARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19. METHODS: ACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596. FINDINGS: Between April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group. INTERPRETATION: Discontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options. FUNDING: Austrian Science Fund and German Center for Cardiovascular Research.


Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , COVID-19 , Hipertensão , Sistema Renina-Angiotensina , SARS-CoV-2 , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Área Sob a Curva , COVID-19/epidemiologia , COVID-19/metabolismo , COVID-19/terapia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Avaliação de Processos e Resultados em Cuidados de Saúde , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Risco Ajustado/métodos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Suspensão de Tratamento/estatística & dados numéricos
20.
Am J Pathol ; 191(7): 1154-1164, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964216

RESUMO

Severe acute respiratory syndrome coronavirus 2, the etiologic agent of coronavirus disease 2019 (COVID-19) and the cause of the current pandemic, produces multiform manifestations throughout the body, causing indiscriminate damage to multiple organ systems, particularly the lungs, heart, brain, kidney, and vasculature. The aim of this review is to provide a new assessment of the data already available for COVID-19, exploring it as a transient molecular disease that causes negative regulation of angiotensin-converting enzyme 2, and consequently, deregulates the renin-angiotensin-aldosterone system, promoting important changes in the microcirculatory environment. Another goal of the article is to show how these microcirculatory changes may be responsible for the wide variety of injury mechanisms observed in different organs in this disease. The new concept of COVID-19 provides a unifying pathophysiological picture of this infection and offers fresh insights for a rational treatment strategy to combat this ongoing pandemic.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Regulação para Baixo , Microcirculação/fisiologia , Sistema Renina-Angiotensina/fisiologia , Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , COVID-19/patologia , Humanos
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