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1.
Clin Sci (Lond) ; 135(1): 1-17, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33399851

RESUMO

The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.


Assuntos
/metabolismo , Cardiopatias/enzimologia , Nefropatias/enzimologia , Angiotensina II/metabolismo , Animais , /metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Cardiopatias/virologia , Humanos , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/virologia , Receptores Virais/genética , Receptores Virais/metabolismo , Sistema Renina-Angiotensina , /fisiologia
2.
Eur Rev Med Pharmacol Sci ; 24(23): 12609-12622, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336781

RESUMO

OBJECTIVE: In human pathology, SARS-CoV-2 utilizes multiple molecular pathways to determine structural and biochemical changes within the different organs and cell types. The clinical picture of patients with COVID-19 is characterized by a very large spectrum. The reason for this variability has not been clarified yet, causing the inability to make a prognosis on the evolution of the disease. MATERIALS AND METHODS: PubMed search was performed focusing on the role of ACE 2 receptors in allowing the viral entry into cells, the role of ACE 2 downregulation in triggering the tissue pathology or in accelerating previous disease states, the role of increased levels of Angiotensin II in determining endothelial dysfunction and the enhanced vascular permeability, the role of the dysregulation of the renin angiotensin system in COVID-19 and the role of cytokine storm. RESULTS: The pathological changes induced by SARS-CoV-2 infection in the different organs, the correlations between the single cell types targeted by the virus in the different human organs and the clinical consequences, COVID-19 chronic pathologies in liver fibrosis, cardiac fibrosis and atrial arrhythmias, glomerulosclerosis and pulmonary fibrosis, due to the systemic fibroblast activation induced by angiotensin II are discussed. CONCLUSIONS: The main pathways involved showed different pathological changes in multiple tissues and the different clinical presentations. Even if ACE2 is the main receptor of SARS-CoV-2 and the main entry point into cells for the virus, ACE2 expression does not always explain the observed marked inter-individual variability in clinical presentation and outcome, evidencing the complexity of this disorder. The proper interpretation of the growing data available might allow to better classifying COVID-19 in human pathology.


Assuntos
Angiotensina II/metabolismo , /metabolismo , Cardiomiopatias/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Endotélio Vascular/fisiopatologia , Cirrose Hepática/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Trombose/metabolismo , Angiotensina I/metabolismo , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Coagulação Sanguínea , /fisiopatologia , Permeabilidade Capilar , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Miocardite/metabolismo , Miocardite/patologia , Miocardite/fisiopatologia , Sistema Renina-Angiotensina , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Trombose/fisiopatologia , Internalização do Vírus
3.
Adv Chronic Kidney Dis ; 27(5): 404-411, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33308506

RESUMO

Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Lesão Pulmonar Aguda/epidemiologia , Lesão Pulmonar Aguda/imunologia , Angiotensina I/imunologia , Angiotensina I/metabolismo , Angiotensina II/imunologia , Angiotensina II/metabolismo , /epidemiologia , Comorbidade , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fatores de Proteção , /metabolismo , Sistema Renina-Angiotensina , Fatores de Risco , Regulação para Cima
4.
J Pharmacol Sci ; 144(4): 218-228, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070841

RESUMO

Myocardial ischemia initiates a chain of pathological conditions leading to cardiomyocyte death. Therefore, pharmacological treatment to stop ischemia-induced damage is necessary. Fibrates, have been reported to decrease inflammatory markers and to modulate the renin-angiotensin system (RAS). Our aim was to explore if clofibrate treatment, administered one week after myocardial event, decreases MI-induced cardiac damage. Wistar rats were assigned to: 1. Sham or 2. Coronary artery ligation (MI). Seven days after, rats were subdivided to receive vehicle (V) or clofibrate [100 mg/kg (C)] daily for 7 days. Blood samples and left ventricle were analyzed. RAS components [angiotensin II, angiotensin converting enzyme (ACE), and AT1-receptor] decreased in MI-C compared to MI-V, while [Ang-(1-7), bradykinin, ACE-2, and AT2-receptor] raised in response to clofibrate treatment. Oxidative stress markers increased in MI-V rats, a profile reverted in MI-C rats. Nitric oxide (NO) pathway (Akt, eNOS, and NO) exhibits a lower participation in MI-V, but clofibrate raised NO-pathway components and its production. MI-induced fibrosis and structural damage was also improved by clofibrate-treatment. In conclusion, clofibrate administration to 7 days MI-rats exerts an antioxidant, pro-vasodilator expression profile, and anti-fibrotic effect suggesting that PPARα activation can be considered a therapeutic target to improve cardiac condition posterior to ischemia.


Assuntos
Clofibrato/administração & dosagem , Clofibrato/farmacologia , Ventrículos do Coração/metabolismo , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Fibrose , Ventrículos do Coração/patologia , Masculino , Isquemia Miocárdica/patologia , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Fatores de Tempo
6.
Phytomedicine ; 79: 153325, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920289

RESUMO

BACKGROUND: Panax notoginseng (Burk.) F.H. Chen is a traditional medicinal plant widely used to prevent and treat cardiovascular diseases. Ginsenoside Rd (GRd) is a major bioactive component of P. notoginseng, but specific effects on cardiovascular disease-related pathogenic processes are rarely studied, especially vascular endothelial injury. PURPOSE: This study investigated the potential protective efficacy of GRd against nicotine-induced vascular endothelial cell injury, disruption of vascular nitric oxide (NO) signaling, aberrant endothelium-monocyte adhesion, platelet aggregation, and vasoconstriction. STUDY DESIGN/METHODS: Vascular endothelial injury and functional disruption were investigated in cultured human umbilical vein endothelial cells (HUVECs) by biochemical assays for nitric oxide (NO) and angiotensin II (Ang II), immunofluorescence (IF) and western blotting for expression analyses of apoptosis- related proteins, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), Ang II type receptor 1 (AGTR1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappa B (NF-κB). In addition, vascular protection by GRd was examined in nicotine-administered Sprague-Dawley (SD) rats by serum NO and Ang II assays, and by hematoxylin-eosin (HE) and immunostaining of aorta. We also examined effects of GRd on monocyte (THP-1 cells) adhesion assays, adenosine diphosphate (ADP)-induced platelet aggregation, and phenylephrine (PE)-induced vasoconstriction of isolated rat aortic rings. RESULTS: In HUVECs, nicotine significantly suppressed NO production, enhanced Ang II production, downregulated eNOS expression, and upregulated expression levels of AGTR1, TLR4, MyD88, NF-κB, iNOS, Bax/Bcl-2 ratio, cleaved caspase-3, and cytochrome c (cyt c). All of these changes were significantly reversed by GRd. In rats, oral GRd reversed the reduction NO and enhanced Ang II production in serum induced by nicotine administration, and HE staining revealed protection of aortic endothelial cells. In addition, GRd reversed nicotine-mediated enhancement of HUVECs-monocyte adhesion, inhibited ADP-induced platelet aggregation and PE-induced vasoconstriction. CONCLUSION: GRd may prevent nicotine-induced cardiovascular diseases by preserving normal vascular endothelial NO signaling, suppressing platelet aggregation and vasoconstriction, and by preventing endothelial cell-monocyte adhesion.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Ginsenosídeos/farmacologia , Nicotina/toxicidade , Angiotensina II/sangue , Angiotensina II/metabolismo , Animais , Aorta/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ginsenosídeos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor 4 Toll-Like/metabolismo , Triterpenos/química , Vasoconstrição/efeitos dos fármacos
7.
Clin Sci (Lond) ; 134(18): 2489-2501, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32990314

RESUMO

Angiotensin-converting enzyme (ACE) is a zinc membrane metallopeptidase that plays a key role in regulating vasoactive peptide levels and hence cardiovascular activity through its conversion of angiotensin I (Ang I) to Ang II and its metabolism of bradykinin. The discovery of its homologue, ACE2, 20 years ago has led to intensive comparisons of these two enzymes revealing surprising structural, catalytic and functional distinctions between them. ACE2 plays multiple roles not only as a vasopeptidase but also as a regulator of amino acid transport and serendipitously as a viral receptor, mediating the cellular entry of the coronaviruses causing severe acute respiratory syndrome (SARS) and, very recently, COVID-19. Catalytically, ACE2 functions as a monocarboxypeptidase principally converting the vasoconstrictor angiotensin II to the vasodilatory peptide Ang-(1-7) thereby counterbalancing the action of ACE on the renin-angiotensin system (RAS) and providing a cardioprotective role. Unlike ACE, ACE2 does not metabolise bradykinin nor is it inhibited by classical ACE inhibitors. However, it does convert a number of other regulatory peptides in vitro and in vivo. Interest in ACE2 biology and its potential as a possible therapeutic target has surged in recent months as the COVID-19 pandemic rages worldwide. This review highlights the surprising discoveries of ACE2 biology during the last 20 years, its distinctions from classical ACE and the therapeutic opportunities arising from its multiple biological roles.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Angiotensina II/efeitos dos fármacos , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Vasoconstritores/farmacologia
8.
PLoS Biol ; 18(8): e3000808, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817651

RESUMO

Although dysregulation of mitochondrial dynamics has been linked to cellular senescence, which contributes to advanced age-related disorders, it is unclear how Krüppel-like factor 5 (Klf5), an essential transcriptional factor of cardiovascular remodeling, mediates the link between mitochondrial dynamics and vascular smooth muscle cell (VSMC) senescence. Here, we show that Klf5 down-regulation in VSMCs is correlated with rupture of abdominal aortic aneurysm (AAA), an age-related vascular disease. Mice lacking Klf5 in VSMCs exacerbate vascular senescence and progression of angiotensin II (Ang II)-induced AAA by facilitating reactive oxygen species (ROS) formation. Klf5 knockdown enhances, while Klf5 overexpression suppresses mitochondrial fission. Mechanistically, Klf5 activates eukaryotic translation initiation factor 5a (eIF5a) transcription through binding to the promoter of eIF5a, which in turn preserves mitochondrial integrity by interacting with mitofusin 1 (Mfn1). Accordingly, decreased expression of eIF5a elicited by Klf5 down-regulation leads to mitochondrial fission and excessive ROS production. Inhibition of mitochondrial fission decreases ROS production and VSMC senescence. Our studies provide a potential therapeutic target for age-related vascular disorders.


Assuntos
Aneurisma da Aorta Abdominal/genética , Células Endoteliais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mitocôndrias/metabolismo , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Idoso , Angiotensina II/genética , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Senescência Celular/efeitos dos fármacos , Ecocardiografia , Células Endoteliais/patologia , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/deficiência , Cultura Primária de Células , Regiões Promotoras Genéticas , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
10.
Am J Pathol ; 190(10): 2013-2017, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32735889

RESUMO

Coronavirus disease 2019 has markedly varied clinical presentations, with most patients being asymptomatic or having mild symptoms. However, severe acute respiratory disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is common and associated with mortality in patients who require hospitalization. The etiology of susceptibility to severe lung injury remains unclear. Angiotensin II, converted by angiotensin-converting enzyme (ACE) from angiotensin I and metabolized by ACE 2 (ACE2), plays a pivotal role in the pathogenesis of lung injury. ACE2 is identified as an essential receptor for SARS-CoV-2 to enter the cell. The binding of ACE2 and SARS-CoV-2 leads to the exhaustion and down-regulation of ACE2. The interaction and imbalance between ACE and ACE2 result in an unopposed angiotensin II. Considering that the ACE insertion (I)/deletion (D) gene polymorphism contributes to the ACE level variability in general population, in which mean ACE level in DD carriers is approximately twice that in II carriers, we propose a hypothesis of genetic predisposition to severe lung injury in patients with coronavirus disease 2019. It is plausible that the ACE inhibitors and ACE receptor blockers may have the potential to prevent and to treat the acute lung injury after SARS-CoV-2 infection, especially for those with the ACE genotype associated with high ACE level.


Assuntos
Infecções por Coronavirus , Predisposição Genética para Doença , Lesão Pulmonar/etiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Frequência do Gene , Genótipo , Humanos , Lesão Pulmonar/virologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Polimorfismo Genético , Receptores Virais/metabolismo , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia
11.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L596-L602, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783619

RESUMO

A new form of severe acute respiratory syndrome (SARS) caused by SARS-coronavirus 2 (CoV-2), called COVID-19, has become a global threat in 2020. The mortality rate from COVID-19 is high in hypertensive patients, making this association especially dangerous. There appears to be a consensus, despite the lack of experimental data, that angiotensin II (ANG II) is linked to the pathogenesis of COVID-19. This process may occur due to acquired deficiency of angiotensin-converting enzyme 2 (ACE2), resulting in reduced degradation of ANG II. Furthermore, ANG II has a critical role in the genesis and worsening of hypertension. In this context, the idea that there is a surge in the level of ANG II with COVID-19 infection, causing multiple organ injuries in hypertensive patients becomes attractive. However, the role of other components of the renin angiotensin system (RAS) in this scenario requires elucidation. The identification of other RAS components in COVID-19 hypertension may provide both diagnostic and therapeutic benefits. Here, we summarize the pathophysiologic contributions of different components of RAS in hypertension and their possible correlation with poor outcome observed in hypertensive patients with COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Betacoronavirus , Infecções por Coronavirus/mortalidade , Humanos , Hipertensão/mortalidade , Pandemias , Pneumonia Viral/mortalidade , Fatores de Risco
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(7): 616-621, 2020 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-32727646

RESUMO

Objective To explore the role of Cx43 in the proliferation and migration of human pulmonary arterial smooth muscle cells (HPASMCs) induced by angiotensin II (Ang II). Methods HPASMCs were cultured in vitro and randomly divided into four groups: control group, Ang II group, Ang II combined with DMSO group, and Ang II combined with candesartan group, and cells were collected in logarithmic growth phase. Cell viability was detected by CCK-8 assay; the migration ability of HPASMCs were measured by wound-healing and TranswellTM assay. The protein levels of Cx43, osteopontin (OPN), proliferating cell nuclear antigen (PCNA), SMAD2 and SMAD3 in HPASMCs were detected by Western blot analysis. Results Compared with the control group, the expression of OPN and PCNA proteins significantly went up in Ang II group, and the cell proliferation and migration ability increased. The cell proliferation and migration ability of the Ang II combined with candesartan group were significantly lower than that in the Ang II group. Compared with the control group, the Cx43 protein and its phosphorylation level increased significantly in the Ang II group, and the protein expression of SMAD2 and SMAD3 increased, while the expression of each protein in the Ang II combined with candesartan group was significantly lower than those in the Ang II group. Conclusion Ang II up-regulates the expression of Cx43 protein to promote the proliferation and migration of HPASMCs, which may be related to the activation of SMAD2/3 signaling pathway.


Assuntos
Proliferação de Células , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Movimento Celular , Células Cultivadas , Conexina 43/metabolismo , Humanos , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Regulação para Cima
13.
J Cardiothorac Surg ; 15(1): 160, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615991

RESUMO

BACKGROUND: To determine whether all-trans retinoic acid (ATRA) can influence the development of Angiotensin II (Ang II) induced experimental abdominal aortic aneurysms (AAAs). METHODS: Apolipoprotein E knock-out (ApoE-/-) mice were randomly assigned to 4 groups. Mice in the AAA and ATRA groups underwent continuous subcutaneous Ang II infusion for 28 days to induce AAA, while the Sham and Control groups were infused with saline. Systolic blood pressure was measured by the tail-cuff technique. The Control and ATRA groups received ATRA treatment. Aortic tissue samples were obtained at 28 days after surgery and evaluated by aortic diameter measurement, Western blotting, immunohistochemistry, and hematoxylin-eosin (H&E) and Verhoeff-Van Gieson (EVG) staining. RESULTS: The abdominal aortic diameter was significantly reduced in the ATRA group compared with the AAA group (3 of 12 (25%) vs 9 of 12 (75%), P < 0.05), and the ATRA group exhibited reduced blood pressure on days 7, 14, and 28. Low expression of angiotensin II receptor type 1 (AT1), matrix metalloproteinase 2 (MMP2), and matrix metalloproteinase 9 (MMP9) and EVG staining revealed a significant reduction in the disruption of elastic fibers in the abdominal aortic tissue of the ATRA group compared to the AAA group. Western blot analysis indicated that protein levels of retinoic acid receptor α (RARα), MMP2, MMP9, and AT1 were dramatically affected by ATRA treatment. CONCLUSIONS: In conclusion, ATRA attenuates the progression of Ang II-induced AAAs, possibly by downregulating MMP2, MMP9, and AT-1 expression.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Tretinoína/farmacologia , Angiotensina II/metabolismo , Animais , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Progressão da Doença , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout para ApoE
14.
J Ovarian Res ; 13(1): 79, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32684166

RESUMO

The outbreak and continued spread of the novel coronavirus disease 2019 (COVID-19) is a preeminent global health threat that has resulted in the infection of over 11.5 million people worldwide. In addition, the pandemic has claimed the lives of over 530,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy, with cancer patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 due to the reported interference in viral S-protein to host receptor binding and its lack of effect on ACE2 expression in the lungs.


Assuntos
Angiotensina II/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Vitanolídeos/farmacologia , Angiotensina II/metabolismo , Animais , Betacoronavirus/metabolismo , Caquexia/metabolismo , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Pandemias , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Diabetes ; 69(9): 1875-1886, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32669391

RESUMO

Individuals with diabetes suffering from coronavirus disease 2019 (COVID-19) exhibit increased morbidity and mortality compared with individuals without diabetes. In this Perspective, we critically evaluate and argue that this is due to a dysregulated renin-angiotensin system (RAS). Previously, we have shown that loss of angiotensin-I converting enzyme 2 (ACE2) promotes the ACE/angiotensin-II (Ang-II)/angiotensin type 1 receptor (AT1R) axis, a deleterious arm of RAS, unleashing its detrimental effects in diabetes. As suggested by the recent reports regarding the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), upon entry into the host, this virus binds to the extracellular domain of ACE2 in nasal, lung, and gut epithelial cells through its spike glycoprotein subunit S1. We put forth the hypothesis that during this process, reduced ACE2 could result in clinical deterioration in COVID-19 patients with diabetes via aggravating Ang-II-dependent pathways and partly driving not only lung but also bone marrow and gastrointestinal pathology. In addition to systemic RAS, the pathophysiological response of the local RAS within the intestinal epithelium involves mechanisms distinct from that of RAS in the lung; however, both lung and gut are impacted by diabetes-induced bone marrow dysfunction. Careful targeting of the systemic and tissue RAS may optimize clinical outcomes in subjects with diabetes infected with SARS-CoV-2.


Assuntos
Angiotensina II/metabolismo , Betacoronavirus/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Medula Óssea/metabolismo , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Humanos , Mucosa Intestinal/metabolismo , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença
16.
Am J Physiol Renal Physiol ; 319(2): F345-F357, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715763

RESUMO

Angiotensin II (ANG II) is the key contributor to renal fibrosis and injury. The present study investigated the role of endothelium prolyl hydroxylase 2 (PHD2) in ANG II-mediated renal fibrosis and injury. In vitro, endothelial cells (ECs) were isolated from PHD2f/f control [wild-type (WT)] mice or PHD2 EC knockout (PHD2ECKO) mice. In vivo, WT and PHD2ECKO mice were infused with ANG II (1,000 ng·kg-1·min-1) for 28 days. Renal fibrosis, reactive oxygen species (ROS), and iron contents were measured. Knockout of PHD2 resulted in a significant increase in the expression of hypoxia-inducible factor (HIF)-1α and HIF-2α in ECs. Intriguingly, knockout of PHD2 significantly reduced expression of the ANG II type 1 receptor (AT1R) in ECs. WT mice infused with ANG II caused increases in renal fibrosis, ROS formation, and iron contents. ANG II treatment led to a downregulation of PHD1 expression and upregulation of HIF-1α and HIF-2α in the renal cortex and medulla. Knockout of PHD2 in EC blunted ANG II-induced downregulation of PHD1 expression. Furthermore, knockout of PHD2 in ECs attenuated ANG II-induced expression of HIF-1α, HIF-2α, transforming growth factor-ß1, p47phox, gp91phox, heme oxygenase-1, and ferroportin. This was accompanied by a significant suppression of renal fibrosis, ROS formation, and iron accumulation. In summary, knockout of endothelial PHD2 suppressed the expression of AT1R in ECs and blunted ANG II-induced downregulation of PHD1 and upregulation of HIF-α in the kidney. Our study, for the first time, demonstrates a necessary role of endothelial PHD2 in ANG II-mediated renal fibrosis and injury.


Assuntos
Angiotensina II/metabolismo , Células Endoteliais/metabolismo , Fibrose/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Nefropatias/enzimologia , Rim/lesões , Angiotensina II/farmacologia , Animais , Células Endoteliais/efeitos dos fármacos , Endotélio/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Rim/enzimologia , Camundongos , Camundongos Knockout , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , RNA Interferente Pequeno/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 40(9): 2108-2113, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640904

RESUMO

OBJECTIVE: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT-/-) mice in an LDL receptor-deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]). Expression of human angiotensinogen in hepAGT-/- mice led to high plasma human angiotensinogen concentrations without changes in plasma endogenous mouse angiotensinogen, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human angiotensinogen not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human angiotensinogen lead to the inability of mouse renin to cleave human angiotensinogen, hepAGT-/- mice were injected with adenoassociated viral vector encoding mouse angiotensinogen (L11V;Y12I). Expression of mouse angiotensinogen (L11V;Y12I) in hepAGT-/- mice resulted in increased plasma mouse angiotensinogen concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse angiotensinogen variant increased blood pressure and atherosclerosis in hepAGT-/- mice to the magnitude of hepAGT+/+ mice. CONCLUSIONS: Replacement of L11 and Y12 to V11 and I12, respectively, in mouse angiotensinogen does not affect renin cleavage, blood pressure, and atherosclerosis in LDL receptor-deficient mice.


Assuntos
Angiotensina II/metabolismo , Angiotensinogênio/metabolismo , Aterosclerose/metabolismo , Pressão Sanguínea , Hepatócitos/metabolismo , Hipertensão/metabolismo , Renina/metabolismo , Substituição de Aminoácidos , Angiotensinogênio/deficiência , Angiotensinogênio/genética , Animais , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Especificidade da Espécie
18.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32652001

RESUMO

The current COVID-19 pandemic is the most disruptive event in the past 50 years, with a global impact on health care and world economies. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a coronavirus that uses angiotensin-converting enzyme 2 (ACE2) as an entry point to the cells. ACE2 is a transmembrane carboxypeptidase and member of the renin-angiotensin system. This mini-review summarizes the main findings regarding ACE2 expression and function in endocrine tissues. We discuss rapidly evolving knowledge on the potential role of ACE2 and SARS coronaviruses in endocrinology and the development of diabetes mellitus, hypogonadism, and pituitary and thyroid diseases.


Assuntos
Angiotensina II/metabolismo , Betacoronavirus/fisiologia , Complicações do Diabetes/virologia , Doenças do Sistema Endócrino/virologia , Peptidil Dipeptidase A/fisiologia , Animais , Betacoronavirus/patogenicidade , Encéfalo , Infecções por Coronavirus/complicações , Doenças do Sistema Endócrino/complicações , Expressão Gênica , Humanos , Hipogonadismo/complicações , Hipogonadismo/virologia , Camundongos , Pandemias , Peptidil Dipeptidase A/genética , Doenças da Hipófise/complicações , Doenças da Hipófise/virologia , Pneumonia Viral/complicações , Ratos , Sistema Renina-Angiotensina , Serina Endopeptidases/genética , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/virologia
19.
Clin Appl Thromb Hemost ; 26: 1076029620938149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32677459

RESUMO

The novel coronavirus infection (COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis, coagulopathy, and death in a proportion of patients. Among other factors and direct viral effects, the increase in the vasoconstrictor angiotensin II, the decrease in the vasodilator angiotensin, and the sepsis-induced release of cytokines can trigger a coagulopathy in COVID-19. A coagulopathy has been reported in up to 50% of patients with severe COVID-19 manifestations. An increase in d-dimer is the most significant change in coagulation parameters in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter indicating a worse outcome. Limited data suggest a high incidence of deep vein thrombosis and pulmonary embolism in up to 40% of patients, despite the use of a standard dose of low-molecular-weight heparin (LMWH) in most cases. In addition, pulmonary microvascular thrombosis has been reported and may play a role in progressive lung failure. Prophylactic LMWH has been recommended by the International Society on Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH), but the best effective dosage is uncertain. Adapted to the individual risk of thrombosis and the d-dimer value, higher doses can be considered, especially since bleeding events in COVID-19 are rare. Besides the anticoagulant effect of LMWH, nonanticoagulant properties such as the reduction in interleukin 6 release have been shown to improve the complex picture of coagulopathy in patients with COVID-19.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Trombofilia/etiologia , Trombose/prevenção & controle , Angiotensina II/metabolismo , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/epidemiologia , Arteriopatias Oclusivas/etiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/etiologia , Surtos de Doenças , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/prevenção & controle , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinolíticos/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Incidência , Inflamação , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Prognóstico , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Risco , Sepse/sangue , Sepse/complicações , Síndrome Respiratória Aguda Grave/sangue , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/epidemiologia , Trombofilia/sangue , Trombofilia/tratamento farmacológico , Trombose/sangue , Trombose/epidemiologia , Trombose/etiologia , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/prevenção & controle , Ativador de Plasminogênio Tecidual/uso terapêutico
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