RESUMO
Coronavirus disease 2019 (Covid-19) has affected millions of people and may disproportionately affect those with hypertension and diabetes. Because of inadequate methods in published systematic reviews, the prevalence of diabetes and hypertension and associated risks of poor outcomes in Covid-19 patients are unknown. We searched databases from December 1, 2019, to April 6, 2020, and selected observational peer-reviewed studies in English of patients with Covid-19. Independent reviewers extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence. We included 65 (15â 794 participants) observational studies at moderate to high risk of bias. Overall prevalence of diabetes and hypertension was 12% (95% confidence interval [CI], 10-15; nâ =â 12â 870; I 2: 89%), and 17% (95% CI, 13-22; nâ =â 12â 709; I 2: 95%), respectively. In severe Covid-19, the prevalence of diabetes and hypertension were 18% (95% CI, 16-20; nâ =â 1099; I 2: 0%) and 32% (95% CI, 16-54; nâ =â 1078; I 2: 63%), respectively. Unadjusted relative risk for intensive care unit admission and mortality were 1.96 (95% CI, 1.19-3.22; nâ =â 8890; I 2: 80%; Pâ =â .008) and 2.78 (95% CI, 1.39-5.58; nâ =â 2058; I 2: 75%; Pâ =â .0004) for diabetics; and 2.95 (95% CI, 2.18-3.99; nâ =â 1737; I 2: 0%; Pâ <â .001) and 2.39 (95% CI, 1.54-3.73; nâ =â 3107; I 2: 66%; Pâ <â .001) for hypertensives. Neither diabetes (1.50; 95% CI, 0.90-2.50; nâ =â 1991; I 2: 74%; Pâ =â .119) nor hypertension (1.48; 95% CI, 0.99-2.23; nâ =â 2023; I 2: 69%; Pâ =â .058) was associated with severe Covid-19. In conclusion, the risk of intensive care unit admission and mortality for patients with diabetes or hypertension who developed Covid-19 is increased compared with those without these comorbidities. PROSPERO REGISTRATION NUMBER: CRD42020176582.
RESUMO
Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS) playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension.
RESUMO
Angiotensin (Ang)-(1-7), acting through the Mas receptor, opposes the actions of Ang II. Molecular mechanisms for this are unclear. Here we sought to determine whether Ang-(1-7) influences Ang II signaling in human endothelial cells, focusing specifically on Src homology 2-containing inositol phosphatase 2 (SHP-2) and its interaction with c-Src. Ang II-induced phosphorylation of c-Src, extracellular signal regulated kinase (ERK)1/2, and SHP-2 and activation of NAD(P)H oxidase were assessed in the absence and presence of Ang-(1-7) (10(-6) mol/L, 15 minutes) by immunoblotting and lucigenin-enhanced chemiluminescence, respectively. (D-Ala(7))-Ang I/II (1-7) (Ang fragment 1-7 receptor antagonist) was used to block Ang-(1-7) effects. Association between SHP-2 and c-Src was assessed by immunoprecipitation/immunoblotting studies. Ang II significantly increased activation of c-Src, ERK1/2, and NAD(P)H oxidase and reduced phosphorylation of SHP-2 (P<0.05) in human endothelial cells. These effects were abrogated in cells pre-exposed to Ang-(1-7). Ang fragment 1-7 receptor antagonist pretreatment blocked the negative modulatory actions of Ang-(1-7) on Ang II-induced signaling. Ang-(1-7) alone did not significantly alter phosphorylation of c-Src, ERK1/2, and SHP-2 and had no effect on basal activity of NAD(P)H oxidase. SHP-2 and c-Src were physically associated in the basal state. This association was increased by Ang-(1-7) and blocked by Ang fragment 1-7 receptor antagonist. Our findings demonstrate that, in human endothelial cells, Ang-(1-7) negatively modulates Ang II/Ang II type 1 receptor-activated c-Src and its downstream targets ERK1/2 and NAD(P)H oxidase. We also show that SHP-2-c-Src interaction is enhanced by Ang-(1-7). These phenomena may represent a protective mechanism in the endothelium whereby potentially deleterious effects of Ang II are counterregulated by Ang-(1-7).
Assuntos
Angiotensina II/antagonistas & inibidores , Angiotensina I/farmacologia , Células Endoteliais/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Transdução de Sinais/fisiologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Proteína Tirosina Quinase CSK , Células Cultivadas , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , NADPH Oxidases/metabolismo , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Quinases da Família srcRESUMO
Angiotensin-(1-7) [Ang-(1-7)] causes endothelial-dependent vasodilation mediated, in part, by NO release. However, the molecular mechanisms involved in endothelial NO synthase (eNOS) activation by Ang-(1-7) remain unknown. Using Chinese hamster ovary cells stably transfected with Mas cDNA (Chinese hamster ovary-Mas), we evaluated the underlying mechanisms related to receptor Mas-mediated posttranslational eNOS activation and NO release. We further examined the Ang-(1-7) profile of eNOS activation in human aortic endothelial cells, which constitutively express the Mas receptor. Chinese hamster ovary-Mas cells and human aortic endothelial cell were stimulated with Ang-(1-7; 10(-7) mol/L; 1 to 30 minutes) in the absence or presence of A-779 (10(-6) mol/L). Additional experiments were performed in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin (10(-6) mol/L). Changes in eNOS (at Ser1177/Thr495 residues) and Akt phosphorylation were evaluated by Western blotting. NO release was measured using both the fluorochrome 2,3-diaminonaphthalene and an NO analyzer. Ang-(1-7) significantly stimulated eNOS activation (reciprocal phosphorylation/dephosphorylation at Ser1177/Thr495) and induced a sustained Akt phosphorylation (P<0.05). Concomitantly, a significant increase in NO release was observed (2-fold increase in relation to control). These effects were blocked by A-779. Wortmannin suppressed eNOS activation in both Chinese hamster ovary-Mas and human aortic endothelial cells. Our findings demonstrate that Ang-(1-7), through Mas, stimulates eNOS activation and NO production via Akt-dependent pathways. These novel data highlight the importance of the Ang-(1-7)/Mas axis as a putative regulator of endothelial function.
Assuntos
Angiotensina I/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fragmentos de Peptídeos/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Angiotensina I/farmacologia , Animais , Aorta/citologia , Células CHO/metabolismo , Células Cultivadas , Cricetinae , Cricetulus , Células Endoteliais/metabolismo , Ativação Enzimática/fisiologia , Humanos , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação , Processamento de Proteína Pós-Traducional/fisiologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/genética , Receptores Acoplados a Proteínas G/genética , TransfecçãoRESUMO
The present study evaluated the effects of endothelin (ET)-1 and the peroxisome proliferator activated receptor gamma (PPAR-gamma) agonist, rosiglitazone, on inflammatory markers in vascular smooth muscle cells (VSMCs) from normotensive (WKY) and hypertensive (SHRSP) rats. Rat VSMC-derived mesenteric arteries from WKY and SHRSP were treated with ET-1 (100 mmol/L) and rosiglitazone (1mumol/L) or ET type A (ET(A)) or type B (ET(B)) receptor antagonists. Nuclear factor kappa-B (NFkappaB) binding activity was assessed by electrophoretic mobility shift assay and phospho-inhibitory kappaB (IkappaB); vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and cyclooxygenase (COX)-2 expression was determined using Western blotting. ET-1 significantly increased NFkappaB binding, and VCAM-1, ICAM, and COX-2 expression to a greater degree in SHRSP than in WKY VSMC. These changes were associated with increased phosphorylation of IkappaB, thus resulting in decreased NFkappaB inhibition. Co-incubation with PPAR-gamma activator rosiglitazone, or ET(A) or ET(B) receptor antagonism prevented ET-1-stimulated vascular proinflammatory effects in both WKY and SHRSP VSMC. Proinflammatory effects of ET-1 in VSMCs are mediated via both ET(A) and ET(B) receptor subtypes. These effects may be abrogated by the PPAR-gamma activator rosiglitazone. PPAR-gamma activators may thus prevent deleterious ET-1-dependent proinflammatory vascular effects in VSMC in hypertension.
RESUMO
OBJECTIVE: We investigated whether angiotensin II (Ang II)-induced reactive oxygen species (ROS) generation is altered in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) during the phases of prehypertension, developing hypertension, and established hypertension and assessed the putative role of insulinlike growth factor-1 receptor (IGF-1R) in Ang II-mediated actions. METHODS: The VSMCs from SHR and Wistar-Kyoto rats (WKY) aged 4 (prehypertensive), 9 (developing hypertension), and 16 (established hypertension) weeks were studied. The ROS production and NAD(P)H oxidase activation were determined by fluorescence and chemiluminescence, respectively. The role of IGF-1R was assessed with the selective inhibitor AG1024. The ROS bioavailability was manipulated with Tiron (10(-5) mol/L) and diphenylene iodonium (DPI) (10(-6) mol/L). RESULTS: Angiotensin II dose dependently increased ROS production in WKY and SHR at all ages. The Ang II-induced responses were greater in SHR versus WKY at 9 and 16 weeks (P < .05). The Ang II-stimulated ROS increase was greater in 9- and 16-week-old SHR versus 4-week SHR (P < .05). These effects were reduced by AG 1024. Basal NAD(P)H oxidase activity was higher in VSMCs from 9-week-old SHR versus 4-week-old rats (P < .05). Angiotensin II induced a significant increase in oxidase activity in VSMCs from 9- and 16-week-old SHR (P < .001), without influencing responses in cells from 4-week-old SHR. Pretreatment of 9- and 16-week-old SHR cells with AG1024 reduced Ang II-mediated NAD(P)H oxidase activation (P < .05). CONCLUSIONS: Basal and Ang II-induced NAD(P)H-driven ROS generation are enhanced in VSMCs from SHR during development of hypertension, but not in cells from prehypertensive rats. Transactivation of IGF-1R by Ang II may be important in vascular oxidative excess in the development of hypertension in SHR.
Assuntos
Angiotensina II/fisiologia , Hipertensão/metabolismo , Músculo Liso Vascular/metabolismo , NADPH Oxidases/metabolismo , Fatores Etários , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Técnicas de Cultura de Células , Modelos Animais de Doenças , Hipertensão/fisiopatologia , Masculino , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/enzimologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Receptor IGF Tipo 1/fisiologia , Ativação Transcricional/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ETA receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ETA antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ETA antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ETA receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.
Assuntos
Moléculas de Adesão Celular/biossíntese , Desoxicorticosterona/toxicidade , Endotelina-1/fisiologia , Endotélio Vascular/patologia , Hipertensão/patologia , Leucócitos/fisiologia , Receptor de Endotelina A/fisiologia , Cloreto de Sódio na Dieta/toxicidade , Animais , Adesão Celular , Moléculas de Adesão Celular/genética , Quimiotaxia de Leucócito , Compostos de Dansil/farmacologia , Modelos Animais de Doenças , Selectina E/biossíntese , Selectina E/genética , Antagonistas do Receptor de Endotelina A , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/fisiologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão Renovascular/induzido quimicamente , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Inflamação , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Macrófagos/fisiologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Nefrectomia , Selectina-P/biossíntese , Selectina-P/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Molécula 1 de Adesão de Célula Vascular/biossíntese , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
Development and progression of end-organ damage in hypertension have been associated with increased oxidative stress. Superoxide anion accumulation has been reported in deoxycorticosterone acetate (DOCA)-salt hypertension, in which endothelin-1 plays an important role in cardiovascular damage. We hypothesized that blockade of ETA receptors in DOCA-salt rats would decrease oxidative stress. Both systolic blood pressure (SBP, 210+/-9 mm Hg; P<0.05) and vascular superoxide generation in vivo were increased in DOCA-salt (44.9+/-10.3% of ethidium bromide-positive nuclei; P<0.05) versus control uninephrectomized (UniNx) rats (118+/-3 mm Hg; 18.5+/-3%, respectively). In DOCA-salt rats, the ETA antagonist BMS 182874 (40 mg/kg per day PO) lowered SBP (170+/-4 versus UniNx, 120+/-3 mm Hg) and normalized superoxide production (21.7+/-6 versus UniNx, 11.9+/-7%). Vitamin E (200 mg/kg per day PO) decreased superoxide formation in DOCA-salt rats (18.8+/-7%) but did not alter SBP. Oxidative stress in nonstimulated circulating polymorphonuclear cells (PMNs) or in PMNs treated with zymosan, an inducer of superoxide release, was similar in DOCA-salt and UniNx groups. Superoxide formation by PMNs was unaffected by treatment with BMS 182874. Western blot analysis showed increased nitrotyrosine-containing proteins in mesenteric vessels from DOCA-salt compared with UniNX. Treatment with either BMS 182874 or vitamin E abolished the differences in vascular nitrotyrosine-containing proteins between DOCA-salt and UniNX. Maximal relaxation to acetylcholine was decreased in DOCA-salt aortas (75.8+/-4.2% versus UniNx, 95.4+/-1.9%, P<0.05). BMS 182874 treatment increased acetylcholine-induced relaxation in DOCA-salt aortas to 93.5+/-4.5%. These in vivo findings indicate that increased vascular superoxide production is associated with activation of the endothelin system through ETA receptors in DOCA-salt hypertension, in apparently blood pressure-independent fashion.
Assuntos
Antagonistas dos Receptores de Endotelina , Hipertensão/metabolismo , Superóxidos/metabolismo , Tirosina/análogos & derivados , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Arteríolas/anatomia & histologia , Arteríolas/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Técnicas de Cultura , Compostos de Dansil/farmacologia , Desoxicorticosterona , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Neutrófilos/metabolismo , Estresse Oxidativo , Proteínas/química , Ratos , Ratos Wistar , Receptor de Endotelina A , Cloreto de Sódio , Tirosina/análise , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
Aldosterone-induced hypertension is associated with renal damage that may be mediated by endothelin-1 (ET-1). We evaluated whether inflammatory cell infiltration and DNA-binding activity of the transcription factors nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) were increased in kidneys from aldosterone-infused rats. The role of ET-1 in these processes was evaluated by treating rats with the ET(A)-receptor blocker, BMS 182874. Rats were infused with aldosterone (0.75 microg/h) via a mini-osmotic pump and were given 1% NaCl in the drinking water in the absence and presence of BMS 182874 or of the aldosterone receptor blocker, spironolactone. Renal sections were used to assess inflammatory cell infiltration, which was identified immunocytochemically using monoclonal antibodies against macrophages (ED1+). Electrophoretic mobility shift assays evaluated the DNA-binding activity of NF-kappa B and AP-1 in renal tissue. Systolic blood pressure (BP) was increased in the aldosterone-infused group compared with controls (123+/-6 versus 110+/-10 mmHg, P<0.05). BMS 182874 and spironolactone significantly decreased BP (P<0.05). Macrophage infiltration was increased in the kidneys of aldosterone-infused rats compared with controls. Renal binding activity (arbitrary units) of AP-1, in contrast with that of NF-kappa B, increased in aldosterone-infused rats compared with control rats (AP-1, 4.2+/-0.3 versus 1.0+/-0.1, P<0.05; NF-kappa B, 1.6+/-0.5 versus 1.2+/-0.5). BMS 182874 and spironolactone decreased macrophage infiltration (by 70% and 50% respectively) and AP-1 binding activity (1.0+/-0.3 and 0.8+/-0.3 respectively). In conclusion, kidneys from aldosterone-infused rats exhibited macrophage infiltration and increased AP-1 DNA-binding activity. These processes were attenuated by BMS 182874. Our findings suggest that renal damage in aldosterone-dependent hypertension is associated with inflammatory processes that are mediated in part via ET-1.