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Angiotensina II , Hipotensión , Humanos , Hipotensión/tratamiento farmacológico , Angiotensina II/administración & dosificación , Relación Dosis-Respuesta a Droga , Vasoconstrictores/administración & dosificación , Vasoconstrictores/uso terapéutico , Procedimientos Quirúrgicos Operativos/efectos adversos , Masculino , FemeninoRESUMEN
Background: The development of major depressive disorder in patients at end of life often goes undiagnosed, as it is difficult to distinguish from preparatory grief and/or hypoactive delirium in this unique patient population. If this preliminary barrier of appropriate diagnosis is overcome, it can be quite difficult to properly select and adjust pharmacological therapy. Many well-established antidepressants take four to five weeks for maximal effectiveness (which may be far too long of a titration period for patients at end of life), have various contraindications to patients' comorbid chronic conditions (particularly patients with cardiovascular disease), or may simply be ineffective. Case: We present a case report of severe treatment-resistant depression in an end-stage heart failure patient enrolled in hospice care. Discussion: We discuss the potential use of a single low-dose intravenous racemic ketamine infusion to reduce end-of-life suffering related to depression, despite the theoretical contraindication of ketamine use in such patients, in part, due to its sympathomimetic secondary effect.
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Trastorno Depresivo Mayor , Insuficiencia Cardíaca , Cuidados Paliativos al Final de la Vida , Ketamina , Humanos , Ketamina/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/inducido químicamente , Depresión/tratamiento farmacológico , Infusiones Intravenosas , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , MuerteRESUMEN
Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and endothelial dysfunction. We hypothesized that sex differences exist in vascular aging processes and would be attenuated by global deletion of the G protein-coupled estrogen receptor. Blood pressure was measured by tail-cuff plethysmography, pulse wave velocity (PWV) and echocardiography were assessed with high-resolution ultrasound, and small vessel reactivity was measured using wire myography in adult (25 wk) and middle-aged (57 wk) male and female mice. Adult female mice displayed lower blood pressure and PWV, but this sex difference was absent in middle-aged mice. Aging significantly increased PWV but not blood pressure in both sexes. Adult female carotids were more distensible than males, but this sex difference was lost during aging. Acetylcholine-induced relaxation was greater in female than male mice at both ages, and only males showed aging-induced changes in cardiac hypertrophy and function. GPER deletion removed the sex difference in PWV and ex vivo stiffness in adult mice. The sex difference in blood pressure was absent in KO mice and was associated with endothelial dysfunction in females. These findings indicate that the impact of aging on arterial stiffening and endothelial function is not the same in male and female mice. Moreover, nongenomic estrogen signaling through GPER impacted vascular phenotype differently in male and female mice. Delineating sex differences in vascular changes during healthy aging is an important first step in improving early detection and sex-specific treatments in our aging population.NEW & NOTEWORTHY Indices of vascular aging were different in male and female mice. Sex differences in pulse wave velocity, blood pressure, and large artery stiffness were abrogated in middle-aged mice, but the female advantage in resistance artery vasodilator function was maintained. GPER deletion abrogated these sex differences and significantly reduced endothelial function in adult female mice. Additional studies are needed to characterize sex differences in vascular aging to personalize early detection and treatment for vascular diseases.
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Análisis de la Onda del Pulso , Rigidez Vascular , Animales , Presión Sanguínea/fisiología , Arterias Carótidas/diagnóstico por imagen , Femenino , Masculino , Ratones , Receptores Acoplados a Proteínas G/genética , Caracteres Sexuales , Rigidez Vascular/fisiologíaRESUMEN
A large body of evidence implicates the renin-angiotensin system in the pathogenesis of cardiovascular disease. However, not everyone understands that the magnitude of the risk reduction achieved in clinical trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is only a fraction of the residual risk for cardiovascular events and death. This paper addresses limitations of current therapeutic approaches based on renin-angiotensin system blockade for hypertension and cardiovascular disease by illustrating the complex biochemical physiology and mechanism of classical and alternate angiotensin peptide formation. Emerging evidence of alternate mechanisms that bypass both renin and angiotensin-converting enzyme to produce the angiotensins in tissues and cells is not currently universally recognized. Currently available treatment would benefit from further insights to help fully meet the aims of patient care, and the challenge is to delve more deeply into the renin-angiotensin system cascade, with the aim of enhancing therapeutics for renin-angiotensin system inhibition. This article provides a reappraisal of the renin-angiotensin-aldosterone cascade, highlighting newly elucidated intermediary components and interplay, and their consequent implications and relevance for understanding the long-term contribution of angiotensin II in cardiovascular diseases and their therapy.
RESUMEN
We engineered a monoclonal antibody (mAb) against the human C-terminus of angiotensin-(1-12) [h-Ang-(1-12)] and performed a biochemical characterization in concert with direct in vivo and ex vivo (carotid artery strips) assessments of h-Ang-(1-12) vasoconstrictor activity in 78 (36 females) transgenic rats expressing the human angiotensinogen gene [TGR(hAGT)L1623] and 26 (10 female) Sprague Dawley (SD) controls. The mAb shows high specificity in neutralizing angiotensin II formation from h-Ang-(1-12) and did not cross-react with human and rat angiotensins. Changes in arterial pressure and heart rate in Inactin® hydrate anesthetized rats were measured before and after h-Ang-(1-12) injections [dose range: 75-300 pmol/kg i.v.] prior to and 30-60 minutes after administration of the h-Ang-(1-12) mAb. Neutralization of circulating Ang-(1-12) inhibited the pressor action of h-Ang-(1-12), prevented Ang-(1-12) constrictor responses in carotid artery rings in both SD and TGR(hAGT)L1623 rats, and caused a fall in the arterial pressure of male and female transgenic rats. The Ang-(1-12) mAb did not affect the response of comparable dose-related pressor responses to Ang II, pre-immune IgG, or the rat sequence of Ang-(1-12). This h-Ang-(1-12) mAb can effectively suppress the pressor actions of the substrate in the circulation of hypertensive rats or in carotid artery strips from both SD and transgenic rats. The demonstration that this Ang-(1-12) mAb by itself, induced a fall in arterial pressure in transgenic hypertensive rats supports further exploring the potential abilities of Ang-(1-12) mAb in the treatment of hypertension.
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Angiotensinógeno , Hipertensión , Angiotensina I/farmacología , Angiotensina II/farmacología , Angiotensinógeno/genética , Angiotensinógeno/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Presión Sanguínea , Femenino , Humanos , Masculino , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Resumo A prevalência de obesidade e insuficiência cardíaca com fração de ejeção preservada (ICFEP) aumenta significativamente em mulheres na pós-menopausa. Embora a obesidade seja um fator de risco para disfunção diastólica do ventrículo esquerdo (DDFVE), o mecanismo que liga a interrupção da produção de hormônios ovarianos, especialmente o estrogênio, ao desenvolvimento da obesidade, DDFVE, e ICFEP em mulheres em processo de envelhecimento não é claro. Estudos clínicos e epidemiológicos demonstram que mulheres na pós-menopausa com obesidade abdominal (definida pela circunferência de cintura) têm risco maior de desenvolver a ICFEP do que homens ou mulheres sem obesidade abdominal. Este estudo analisa dados clínicos que corroboram a existência de uma ligação de mecanismo entre a perda de estrogênio mais obesidade e o remodelamento ventricular esquerdo com ICFEP. Ele também discute os possíveis mecanismos celulares e moleculares para a proteção mediada por estrogênio contra tipos de células, depósitos de tecidos, função e metabolismo de adipócitos negativos que podem contribuir para a DDFVE e a ICFEP.
Abstract The prevalence of obesity and heart failure with preserved ejection fraction (HFpEF) increases significantly in postmenopausal women. Although obesity is a risk factor for left ventricular diastolic dysfunction (LVDD), the mechanisms that link the cessation of ovarian hormone production, and particularly estrogens, to the development of obesity, LVDD, and HFpEF in aging females are unclear. Clinical, and epidemiologic studies show that postmenopausal women with abdominal obesity (defined by waist circumference) are at greater risk for developing HFpEF than men or women without abdominal obesity. The study presents a review of clinical data that support a mechanistic link between estrogen loss plus obesity and left ventricular remodeling with LVDD. It also seeks to discuss potential cell and molecular mechanisms for estrogen-mediated protection against adverse adipocyte cell types, tissue depots, function, and metabolism that may contribute to LVDD and HFpEF.
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Humanos , Masculino , Femenino , Disfunción Ventricular Izquierda/etiología , Insuficiencia Cardíaca/etiología , Volumen Sistólico , Función Ventricular Izquierda , Estrógenos , Obesidad Abdominal/complicacionesRESUMEN
The prevalence of obesity and heart failure with preserved ejection fraction (HFpEF) increases significantly in postmenopausal women. Although obesity is a risk factor for left ventricular diastolic dysfunction (LVDD), the mechanisms that link the cessation of ovarian hormone production, and particularly estrogens, to the development of obesity, LVDD, and HFpEF in aging females are unclear. Clinical, and epidemiologic studies show that postmenopausal women with abdominal obesity (defined by waist circumference) are at greater risk for developing HFpEF than men or women without abdominal obesity. The study presents a review of clinical data that support a mechanistic link between estrogen loss plus obesity and left ventricular remodeling with LVDD. It also seeks to discuss potential cell and molecular mechanisms for estrogen-mediated protection against adverse adipocyte cell types, tissue depots, function, and metabolism that may contribute to LVDD and HFpEF.
A prevalência de obesidade e insuficiência cardíaca com fração de ejeção preservada (ICFEP) aumenta significativamente em mulheres na pós-menopausa. Embora a obesidade seja um fator de risco para disfunção diastólica do ventrículo esquerdo (DDFVE), o mecanismo que liga a interrupção da produção de hormônios ovarianos, especialmente o estrogênio, ao desenvolvimento da obesidade, DDFVE, e ICFEP em mulheres em processo de envelhecimento não é claro. Estudos clínicos e epidemiológicos demonstram que mulheres na pós-menopausa com obesidade abdominal (definida pela circunferência de cintura) têm risco maior de desenvolver a ICFEP do que homens ou mulheres sem obesidade abdominal. Este estudo analisa dados clínicos que corroboram a existência de uma ligação de mecanismo entre a perda de estrogênio mais obesidade e o remodelamento ventricular esquerdo com ICFEP. Ele também discute os possíveis mecanismos celulares e moleculares para a proteção mediada por estrogênio contra tipos de células, depósitos de tecidos, função e metabolismo de adipócitos negativos que podem contribuir para a DDFVE e a ICFEP.
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Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Estrógenos , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Obesidad Abdominal/complicaciones , Volumen Sistólico , Disfunción Ventricular Izquierda/etiología , Función Ventricular IzquierdaRESUMEN
AIMS: G protein-coupled estrogen receptor 30 (GPR30) activation by its agonist, G1, exhibits beneficial actions in female with heart failure (HF). Recent evidence indicates its cardiovascular benefits may also include male as well. However, whether and how GPR30 activation may limit HF progression and have a salutary role in males is unknown. We hypothesized that chronic G1 treatment improves LV and cardiomyocyte function, [Ca2+]i regulation and ß-adrenergic reserve, thus limiting HF progression in male. MAIN METHODS: We compared left ventricle (LV) and myocyte function, [Ca2+]i transient ([Ca2+]iT) and ß-AR modulation in control male mice (12/group) and isoproterenol-induced HF (150 mg/kg s.c. for 2 days). Two weeks after isoproterenol injection, HF mice received placebo, or G1 (150 µg/kg/day s.c. mini-pump) for 2 weeks. KEY FINDINGS: Isoproterenol-treated mice exhibited HF with preserved ejection fraction (HFpEF) at 2-weeks and progressed to HF with reduced EF (HFrEF) at 4-weeks, manifested by significantly increased LV time constant of relaxation (τ), decreased EF and mitral flow (dV/dtmax), which were accompanied by reduced myocyte contraction (dL/dtmax), relaxation (dR/dtmax) and [Ca2+]iT. Acute isoproterenol-superfusion caused significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. G1 treatment in HF increased basal and isoproterenol-stimulated increases in EF and LV contractility of EES. Importantly, G1 improved basal and isoproterenol-stimulated dL/dtmax, dR/dtmax and [Ca2+]iT to control levels and restored normal cardiac ß-AR subtypes modulation. SIGNIFICANCE: Chronic G1 treatment restores normal myocyte basal and ß-AR-stimulated contraction, relaxation, and [Ca2+]iT, thereby reversing LV dysfunction and playing a rescue role in a male mouse model of HF.
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Insuficiencia Cardíaca/tratamiento farmacológico , Ventrículos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Quinolinas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Isoproterenol , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/fisiología , Quinolinas/farmacologíaRESUMEN
[Figure: see text].
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Presión Sanguínea/fisiología , Arterias Carótidas/fisiopatología , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Rigidez Vascular/fisiología , Animales , Presión Sanguínea/genética , Arterias Carótidas/metabolismo , Ecocardiografía , Femenino , Genotipo , Humanos , Masculino , Ratones Noqueados , Fenotipo , Análisis de la Onda del Pulso , Receptores de Estrógenos/genética , Receptores Acoplados a Proteínas G/genética , Factores Sexuales , Rigidez Vascular/genéticaRESUMEN
BACKGROUND: Knee osteoarthritis (KOA) is increasingly more prevalent and significant number of patients require knee arthroplasty. Although knee arthroplasty is generally successful, it takes months to recover physical function. Preoperative physical function is known to predict postoperative outcomes and exercise can improve preoperative physical function. However, patients with KOA have difficulty exercise on land due to pain and stiffness, while water exercise can be better tolerated. We hypothesized that preoperative water exercise to improve preoperative physical function will improve postoperative outcomes after total knee arthroplasty (TKA). METHODS: We enrolled 43 participants who were scheduled for elective TKA in 4-8 weeks and scored at or below 50th percentile in mobility assessment tool-sf (MAT-sf). All enrolled participants were assessed on 1) clinical osteoarthritis symptom severity using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 2) physical function using Short Physical Performance Battery (SPPB), 3) self-reported mobility using Mobility Assessment Tool-short form (MAT-sf), 4) depression using Geriatric Depression Scale-short form (GDS-sf), 5) cognitive function using Montreal Cognitive Assessment (MoCA). Blood samples for high-sensitivity-C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were stored at - 80 °C then all samples were analyzed together. All the enrolled participants were randomly assigned to the aquatic exercise intervention (AEI) or usual care group. Sixty minute sessions of AEI was conducted three times a week for 4-8 weeks. Participants in both groups were evaluated within 1 week before their scheduled surgery, as well as 4 weeks after the surgery. RESULTS: The mean age was 67.1 (±6.2), 44% were female, 74% were White. There is no statistically significant difference in combined outcome of any complication, unscheduled ER visit, and disposition to nursing home or rehab facility by AEI. However, AEI was associated with more favorable outcomes: WOMAC scores (p < 0.01), chair-stand (p = 0.019), MAT-sf as well as improved depression (p = 0.043) and cognition (p = 0.008). CONCLUSION: 4-8 weeks of aquatic exercise intervention resulted in improved functional outcomes as well as improved depression and cognition in elderly patients undergoing TKA. A larger study is warranted to explore the role of water exercise in clinical and functional outcomes of TKA.
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Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Rodilla , Adulto , Anciano , Artroplastia de Reemplazo de Rodilla/efectos adversos , Terapia por Ejercicio , Femenino , Humanos , Masculino , Osteoartritis de la Rodilla/diagnóstico , Osteoartritis de la Rodilla/cirugía , Proyectos Piloto , Ejercicio Preoperatorio , Resultado del TratamientoRESUMEN
G protein-coupled estrogen receptor (GPER) activation by G1 attenuates diastolic dysfunction from estrogen loss, which may be partly due to suppression of angiotensin II pathological actions. We aimed to determine the independent effects of 8 weeks of G1 (100 µg/kg/d, subcutaneous pellet), ACE-inhibition (ACEi; lisinopril 10 mg/kg, drinking water), or combination therapy versus vehicle in the ovariectomized (OVX) spontaneously hypertensive rat (SHR) on cardiac function and morphometrics (echocardiography), serum equilibrium of angiotensins (mass spectroscopy) and cardiac components of the RAS (Western blotting). G1 alone and when combined with ACEi enhanced myocardial relaxation (é: 30 and 17%) and diastolic wall strain (DWS: 76 and 68%) while reducing relative wall thickness (RWT: 20 and 33%) and filling pressures (E/é: 30 and 37%). Cardiac expression levels of Mas receptor (Mas-R) and ACE2 also increased in the presence of G1. Strong antihypertensive effects of lisinopril monotherapy were associated with reductions in RWT, collagen deposition and E/é without overtly altering é or DWS. Chronic ACEi also increased cardiac levels of Mas-R and AT1-R and tilted the circulating RAS toward the formation of Ang-(1-7), which was amplified in the presence of G1. In vitro studies further revealed that an inhibitor to prolyl endopeptidase (PEP), but not to neprilysin, significantly reduced serum Ang-(1-7) levels in G1-treated rats, suggesting that G1 might be increasing Ang-(1-7) formation via PEP. We conclude that activating GPER with G1 augments components of the cardiac RAS and improves diastolic function without lowering blood pressure, and that lisinopril-induced blood pressure control and cardiac alterations in OVX SHR are permissive in facilitating G1 to augment Ang-(1-7) in serum, thereby strengthening its cardioprotective benefits.
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Angiotensina I/fisiología , Ciclopentanos/farmacología , Diástole/efectos de los fármacos , Lisinopril/farmacología , Fragmentos de Péptidos/fisiología , Quinolinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Angiotensina I/sangre , Animales , Femenino , Ovariectomía , Fragmentos de Péptidos/sangre , Ratas , Ratas Endogámicas SHR , Receptores Acoplados a Proteínas G/fisiología , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiologíaRESUMEN
The dodecapeptide angiotensin-(1-12) [Ang-(1-12)] functions as an intracrine/paracrine substrate for local production of angiotensin II. We developed a reliable and specific radioimmunoassay (RIA) method for the measurement of Ang-(1-12) in human plasma and urine using an affinity purified antibody fraction directed towards the C-terminus of the human Ang-(1-12) sequence. The RIA method was applied to quantify the Ang-(1-12) in plasma and urine collected from thirty-four human subjects (29 treated with antihypertensive medicines and 5 untreated patients). Plasma Ang-(1-12) level was significantly higher (P < 0.05) in patients with systolic blood pressure ≥140 mm Hg (n = 10) compared to the group with systolic blood pressure <140 mm Hg (n = 24). No significant difference (P = 0.22) was found in spot urine between the groups. Our study also shows that the polyclonal antibody neutralizes the cleavage sites of the human Ang-(1-12) from recombinant human chymase (rhChymase) and serum angiotensin converting enzyme (ACE) mediated Ang II generating hydrolysis. Overall, this newly developed RIA method is reliable and applicable to accurately quantify the Ang-(1-12) level in clinical samples (plasma and urine). Further, our in vitro neutralization study suggests that the anti-Ang-(1-12)-antibody might be used as an in vivo therapeutic agent for preventing Ang-(1-12)/Ang II-mediated hypertension and organ damage.
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Angiotensinógeno/sangre , Angiotensinógeno/orina , Hipertensión/genética , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/orina , Radioinmunoensayo/métodos , Sistema Renina-Angiotensina/genética , Anciano , Angiotensina II/sangre , Angiotensina II/genética , Angiotensina II/orina , Angiotensinógeno/genética , Anticuerpos/química , Anticuerpos/aislamiento & purificación , Antihipertensivos/uso terapéutico , Presión Sanguínea/genética , Estudios de Casos y Controles , Quimasas/sangre , Quimasas/genética , Femenino , Regulación de la Expresión Génica , Humanos , Hipertensión/sangre , Hipertensión/tratamiento farmacológico , Hipertensión/orina , Límite de Detección , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/genética , Radioinmunoensayo/normas , Proteínas Recombinantes/sangre , Proteínas Recombinantes/genética , Transducción de Señal , Equilibrio Hidroelectrolítico/genéticaRESUMEN
PURPOSE OF REVIEW: Hospitalizations for COVID-19 dramatically increase with age. This is likely because of increases in fragility across biological repair systems and a weakened immune system, including loss of the cardiorenal protective arm of the renin--angiotensin system (RAS), composed of angiotensin-converting enzyme-2 (ACE2)/angiotensin-(1--7) [Ang-(1--7)] and its actions through the Mas receptor. The purpose of this review is to explore how cardiac ACE2 changes with age, cardiac diseases, comorbid conditions and pharmaceutical regimens in order to shed light on a potential hormonal unbalance facilitating SARs-CoV-2 vulnerabilities in older adults. RECENT FINDINGS: Increased ACE2 gene expression has been reported in human hearts with myocardial infarction, cardiac remodeling and heart failure. We also found ACE2 mRNA in atrial appendage tissue from cardiac surgical patients to be positively associated with age, elevated by certain comorbid conditions (e.g. COPD and previous stroke) and increased in conjunction with patients' chronic use of antithrombotic agents and thiazide diuretics but not drugs that block the renin--angiotensin system. SUMMARY: Cardiac ACE2 may have bifunctional roles in COVID-19 as ACE2 not only mediates cellular susceptibility to SARS-CoV-2 infection but also protects the heart via the ACE2/Ang-(1--7) pathway. Linking tissue ACE2 from cardiac surgery patients to their comorbid conditions and medical regimens provides a unique latform to address the influence that altered expression of the ACE2/Ang-(1-7)/Mas receptor axis might have on SARs-CoV-2 vulnerability in older adults.
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Apéndice Atrial , COVID-19 , Procedimientos Quirúrgicos Cardíacos , Anciano , Envejecimiento , Enzima Convertidora de Angiotensina 2 , Angiotensinas , Apéndice Atrial/cirugía , Humanos , SARS-CoV-2Asunto(s)
Proteína ADAM17/biosíntesis , Proteína ADAM17/genética , Enzima Convertidora de Angiotensina 2/biosíntesis , Enzima Convertidora de Angiotensina 2/genética , COVID-19/genética , COVID-19/metabolismo , Atrios Cardíacos/metabolismo , Receptores de Estrógenos/metabolismo , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/genética , Femenino , Humanos , Premenopausia , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/genética , Receptores Acoplados a Proteínas G/biosíntesis , Receptores Acoplados a Proteínas G/genética , Sistema Renina-AngiotensinaRESUMEN
The importance of canonical versus noncanonical mechanisms for the generation of angiotensins remains a major challenge that, in part, is heavily swayed by the relative efficacy of therapies designed to inhibit renin, ACE (angiotensin-converting enzyme), or the Ang II (Angiotensin II) receptor. Ang (1-12) (angiotensin [1-12]) is an Ang II forming substrate serving as a source for Ang II-mediated tissue actions. This study identifies for the first time the presence of Ang (1-12) in the blood of 52 normal (22 women) and 19 (13 women) patients with hypertension not receiving antihypertensive medication at the time of the study. Normal subjects of comparable ages and body habitus had similar circulating plasma Ang (1-12) concentrations (women: 2.02±0.62 [SD] ng/mL; men 2.05±0.55 [SD] ng/mL, P>0.05). The higher values of plasma Ang (1-12) concentrations in hypertensive men (2.51±0.49 ng/mL, n=6) and women (2.33±0.63 [SD] ng/mL, n=13) were statistically significant (P<0.02) and correlated with elevated plasma renin activity, systolic and pulse pressure, and plasma concentrations of NT-proBNP (N-terminal prohormone BNP). The increased plasma Ang (1-12) in patients with hypertension was not mirrored by similar changes in plasma angiotensinogen and Ang II concentrations. The first identification of an age-independent presence of Ang (1-12) in the blood of normotensive subjects and patients with hypertension, irrespective of sex, implicates this non-renin dependent substrate as a source for Ang II production in the blood and its potential contribution to the hypertensive process.
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Angiotensinógeno/sangre , Presión Sanguínea/fisiología , Hipertensión/fisiopatología , Fragmentos de Péptidos/sangre , Anciano , Angiotensina II/sangre , Femenino , Humanos , Hipertensión/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Péptido Natriurético Encefálico/sangre , Renina/sangreRESUMEN
The identification of an alternate extended form of angiotensin I composed of the first twelve amino acids at the N-terminal of angiotensinogen has generated new knowledge of the importance of noncanonical mechanisms for renin independent generation of angiotensins. The human sequence of the dodecapeptide angiotensin-(1-12) [N-Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8-His9-Leu10-Val1-Ile12-COOH] is an endogenous substrate that in the rat has been documented to be present in multiple organs including the heart, brain, kidney, gut, adrenal gland, and the bone marrow. Newer studies have confirmed the existence of Ang-(1-12) as an Ang II-forming substrate in the blood and heart of normal and diseased patients. Studies to-date document that angiotensin II generation from angiotensin-(1-12) does not require renin participation while chymase rather than angiotensin converting enzyme shows high catalytic activity in converting this tissue substrate into angiotensin II directly.
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Angiotensina II/metabolismo , Angiotensina I/metabolismo , Angiotensinógeno/metabolismo , Quimasas/metabolismo , Fragmentos de Péptidos/metabolismo , Sistema Renina-Angiotensina/genética , Glándulas Suprarrenales/enzimología , Angiotensina I/genética , Angiotensina II/genética , Angiotensinógeno/genética , Animales , Biocatálisis , Médula Ósea/enzimología , Encéfalo/enzimología , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Quimasas/genética , Expresión Génica , Humanos , Intestinos/enzimología , Riñón/enzimología , Miocardio/enzimología , Fragmentos de Péptidos/genética , RatasRESUMEN
The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/efectos de los fármacos , Neumonía Viral/virología , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/enzimología , Humanos , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/enzimología , SARS-CoV-2 , Factores de TiempoRESUMEN
PURPOSE OF REVIEW: Angiotensin-converting enzyme 2 (ACE2), a specific high-affinity angiotensin II-hydrolytic enzyme, is the vector that facilitates cellular entry of SARS-CoV-1 and the novel SARS-CoV-2 coronavirus. SARS-CoV-2, which crossed species barriers to infect humans, is highly contagious and associated with high lethality due to multi-organ failure, mostly in older patients with other co-morbidities. RECENT FINDINGS: Accumulating clinical evidence demonstrates that the intensity of the infection and its complications are more prominent in men. It has been postulated that potential functional modulation of ACE2 by estrogen may explain the sex difference in morbidity and mortality. We review here the evidence regarding the role of estrogenic hormones in ACE2 expression and regulation, with the intent of bringing to the forefront potential mechanisms that may explain sex differences in SARS-CoV-2 infection and COVID-19 outcomes, assist in management of COVID-19, and uncover new therapeutic strategies.