المؤلفون: Manuel Alejandro Contreras Figueroa, Irene Mendoza Lujambio, Teresa Alvarado Gutiérrez, María Fernanda Pérez Hernández, Evelyn Yazmín Estrada Ramírez, Dominga Jiménez Guzmán, María Fernanda Lucas Sánchez, Hannia Fernanda González Morales, Héctor Jaime Gómez Zamudio, Fernando Suarez Sánchez, Margarita Díaz Flores, Carlos Alberto Jiménez Zamarripa, Claudia Camelia Calzada Mendoza, María Esther Ocharán Hernández, Cora Mariana Orozco Velázquez, Mariana Soto Flores, Daniela Vicenta Hernández Orozco, Gabriela Yanet Cortés Moreno, Miguel Cruz, José de Jesús Peralta Romero

المصدر: Nefrología, Vol 43, Iss 5, Pp 546-561 (2023)

مصطلحات موضوعية: Diabetes mellitus type 2, Diabetic nephropathies, Glomerular Filtration Rate, Single Nucleotide Polymorphism, Angiotensin type 1 receptor, Diseases of the genitourinary system. Urology, RC870-923

الوصف: Resumen: Antecedentes: La búsqueda de biomarcadores tempranos de enfermedad renal diabética (ERD) en pacientes con diabetes mellitus tipo 2 (DMT2), como los marcadores genéticos para identificar pacientes vulnerables de la enfermedad, incluso antes de la presencia de una disminución de la estimación de tasa de filtrado glomerular (TFGe) o presencia de microalbuminuria ha cobrado importancia en los últimos años.El polimorfismo rs5186 (A1166C) presente en el gen receptor tipo 1 de la angiotensina II (AGTR1) ha sido asociado a distintos efectos del riesgo de daño renal que suelen estar presentes en pacientes con diabetes mellitus (DM). Se ha descrito que el rs5186 podría influir en la estabilidad de las proteínas que conforman al receptor de la angiotensina II tipo 1 (AT1) alterando su actividad, por lo que podría ser considerado como un factor de riesgo a enfermedad renal crónica (ERC) caracterizada por una disminución progresiva de la TFG. Sin embargo, la asociación del polimorfismo rs5186 del gen AGTR1 con ERD en pacientes con DMT2 ha sido controversial, no concluyente, incluso nula. Las controversias podrían ser por los estudios de asociación y estimación del riesgo del rs5186 previamente reportados incluyen distintos fenotipos clínicos considerados como inductores y potenciadores de ERC, además, los tamaños de las muestras analizadas en pacientes con DMT2 eran pequeñas y no tenían un control estricto en su inclusión, careciendo incluso de marcadores bioquímicos o estadificación KDOQI que han dificultado su análisis. Objetivo: Determinar la asociación del rs5186 del gen AGTR1 con la disminución de TFGe considerada como riesgo al desarrollo de ERD en pacientes con DMT2. Material y métodos: Se analizaron 297 pacientes con DMT2 no emparentados, divididos en 221 controles (KDOQI 1) y 76 casos (KDOQI 2). Se determinaron parámetros de presión arterial, antropometría y bioquímicos. El genotipado del rs5186 del gen AGTR1 se realizó por PCR en tiempo real con uso de sondas TaqMan. Se determinaron frecuencias alélicas, genotípicas y equilibrio de Hardy-Weinberg. El análisis del comportamiento de los datos se determinó con Shapiro-Wilk, la comparación de las variables por t de Student para variables continuas, y X2 para variables categóricas, se usó prueba ANOVA para comparación de medias de más de dos grupos. El efecto del rs5186 a disminución de TFGe se realizó por distintos modelos de herencia ajustados por variables de riesgo a ERD. Se consideró un valor de p < 0,05 como estadísticamente significativo. Se utilizó el software Statistical Package STATA v11. Resultados: Los modelos dominante y sobredominante mostraron un riesgo a la disminución de la TFGe de 1,89 (1,05-3,39, p = 0,031) y 2,01 (1,08-3,73, p = 0,023) en pacientes con DMT2. El riesgo aumentó a 2,54 (1,10-5,89) en el modelo sobredominante en mujeres. Conclusión: En la práctica clínica, la mayoría de las nefropatías progresan lentamente hacia la pérdida definitiva de la función renal, cursando incluso asintomáticas. El presente estudio es el primero en reportar una contribución del rs5186 del gen AGTR1 con una disminución de la TFGe y podría ser considerado como un riesgo a ERD en pacientes con DMT2. Abstract: Background: Early biomarkers search for Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM), as genetic markers to identify vulnerable carriers of the disease even before Glomerular Filtration Rate (GFR) decline or microalbuminuria development, has been relevant during the last few years.The rs5186 (A116C) polymorphism of the Angiotensin II Receptor Type I gene (AGTR1), has been associated to multiple effects of renal injury risk, commonly detected in patients with Diabetes Mellitus (DM). It has been described that rs5186 could have an effect in stability proteins that assemble Angiotensin II Receptor Type I (AT1), modifying its action, which is why it should be considered as a risk factor for Chronic Kidney Disease (CKD), characterized by a GFR progressive reduction. Even though, the association between rs5186 AGTR1 gene polymorphism and DKD in patients with T2DM has been controversial, inconclusive, and even absent. This disputable issue might be as a result of association studies in which many and varied clinical phenotypes included are contemplated as CKD inductors and enhancers. Although, the sample sizes studied in patients with T2DM are undersized and did not have a strict inclusion criteria, lacking of biochemical markers or KDOQI classification, which have hindered its examination. Objective: The aim of our study was to establish an association between rs5186 AGTR1 gene polymorphism and GFR depletion, assessed as a risk factor to DKD development in patients with T2DM. Methods: We analyzed 297 not related patients with T2DM, divided into 221 controls (KDOQI 1) and 76 cases (KDOQI 2). Arterial pressure, anthropometric and biochemical parameters were measured. rs5186 of AGTR1 genotyping was performed by TaqMan assay real-time PCR method. Allele and genotype frequencies, and Hardy-Weinberg equilibrium were measured. Normality test for data distribution was analyzed by Shapiro-Wilk test, variable comparison by Student's t-test for continuous variables, and Chi-squared test for categorical variables; ANOVA test was used for mean comparison of more than two groups. Effect of rs5186 to DKD was estimated by multiple heritability adjustment models for risk variables of DKD. Statistical significance was indicated by p < 0.05. Data was analyzed using Statistical Package STATA v11 software. Results: Dominant and Over-dominant models showed a likelihood ratio to GFR depletion of 1.89 (1.05-3.39, p = 0.031) and 2.01 (1.08-3.73, p = 0.023) in patients with T2DM. Risk factor increased to 2.54 (1.10-5.89) in women in Over-dominant model. Conclusión: In clinical practice, most of nephropathies progress at a slow pace into a total breakdown of renal function, even asymptomatic. This is the first study, reporting that rs5186 polymorphism of AGTR1 gene contribution to GFR depletion, and this could be evaluated as a predisposing factor for DKD in patients with T2DM.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S0211699522001199Test; https://doaj.org/toc/0211-6995Test

الوصول الحر: https://doaj.org/article/f7d41e5407c941c1bcbd48bf09543121Test

المؤلفون: Tae-Sun Ha, Su-Bin Seong, Dong-Soo Ha, Seung Jung Kim

المصدر: Kidney Research and Clinical Practice, Vol 42, Iss 2, Pp 202-215 (2023)

مصطلحات موضوعية: angiotensin ii, angiotensin type 1 receptor, apoptosis, nadph oxidases, oxidative stress, podocytes, Internal medicine, RC31-1245, Specialties of internal medicine, RC581-951

الوصف: Background Angiotensin II induces glomerular and podocyte injury via systemic and local vasoconstrictive or non-hemodynamic effects including oxidative stress. The release of reactive oxygen species (ROS) from podocytes may participate in the development of glomerular injury and proteinuria. We studied the role of oxidative stress in angiotensin II-induced podocyte apoptosis. Methods Mouse podocytes were incubated in media containing various concentrations of angiotensin II at different incubation times and were transfected with NADH/NADPH oxidase 4 (Nox4) or angiotensin II type 1 receptor for 24 hours. The changes in intracellular and mitochondrial ROS production and podocyte apoptosis were measured according to the presence of angiotensin II. Results Angiotensin II increased the generation of mitochondrial superoxide anions and ROS levels but suppressed superoxide dismutase activity in a dose- and time-dependent manner that was reversed by probucol, an antioxidant. Angiotensin II increased Nox4 protein and expression by a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of Nox4 by small interfering RNA (siRNA) reduced the oxidative stress induced by angiotensin II. Angiotensin II treatment also upregulated AT1R protein. Furthermore, angiotensin II promoted podocyte apoptosis, which was reduced significantly by probucol and Nox4 siRNA and also recovered by angiotensin II type 1 receptor siRNA. Conclusion Our findings suggest that angiotensin II increases the generation of mitochondrial superoxide anions and ROS levels via the upregulation of Nox4 and angiotensin II type 1 receptor. This can be prevented by Nox4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as use of antioxidants.

وصف الملف: electronic resource

العلاقة: http://krcp-ksn.org/upload/pdf/j-krcp-22-198.pdfTest; https://doaj.org/toc/2211-9132Test; https://doaj.org/toc/2211-9140Test

الوصول الحر: https://doaj.org/article/e2550ce7b8d04d2799c533fb6794f883Test

المؤلفون: Yong Zhang, Benard O. Ogola, Laxmi Iyer, Vardan T. Karamyan, Thomas Thekkumkara

المصدر: Frontiers in Physiology, Vol 13 (2022)

مصطلحات موضوعية: heart rate, hypertension, 2-methoxtestradiol, renin angiotensin system, angiotensin type 1 receptor, Physiology, QP1-981

الوصف: The therapeutic potential of 2-Methoxyestradiol (2ME2) is evident in cardiovascular disease. Our laboratory has previously demonstrated the mechanism involved in the 2ME2 regulation of angiotensin type 1 receptor (AT1R) in vitro. However, 2ME2 regulation of angiotensin receptors and its effects on blood pressure (BP) and resting heart rate (RHR) are uncertain. In this study, male and female Wistar-Kyoto (WKY) rats infused with angiotensin II (65 ng/min) and male spontaneously hypertensive rats (SHR) were surgically implanted with telemetric probes to continuously assess arterial BP and RHR. In both male and female WKY rats, 2ME2 treatment (20 mg/kg/day for 2 weeks) resulted in a significant reduction of Ang II-induced systolic, diastolic, and mean arterial BP. Moreover, significant weight loss and RHR were indicated in all groups. In a separate set of experiments, prolonged 2ME2 exposure in male SHR (20 mg/kg/day for 5 weeks) displayed a significant reduction in diastolic and mean arterial BP along with RHR. We also found downregulation of angiotensin receptors and angiotensinogen (AGT) in the kidney and liver and a reduction of plasma Ang II levels. Collectively, we demonstrate that 2ME2 attenuated BP and RHR in hypertensive rats involves downregulation of angiotensin receptors and body weight loss.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fphys.2022.876777/fullTest; https://doaj.org/toc/1664-042XTest

الوصول الحر: https://doaj.org/article/cef8e94fc5a44f83bee0cb06a0837a08Test

المؤلفون: John M. Matsoukas, Laura Kate Gadanec, Anthony Zulli, Vasso Apostolopoulos, Konstantinos Kelaidonis, Irene Ligielli, Kalliopi Moschovou, Nikitas Georgiou, Panagiotis Plotas, Christos T. Chasapis, Graham Moore, Harry Ridgway, Thomas Mavromoustakos

المصدر: Biomedicines; Volume 10; Issue 7; Pages: 1731

مصطلحات موضوعية: angiotensin-converting enzyme 2, angiotensin II, angiotensin type 1 receptor, coronavirus 2019, diminazene aceturate, sartans, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, COVID-19, drug repurposing, DIZE, ACE2

الوصف: Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE’s protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE’s ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.

وصف الملف: application/pdf

العلاقة: Molecular and Translational Medicine; https://dx.doi.org/10.3390/biomedicines10071731Test

الإتاحة: https://doi.org/10.3390/biomedicines10071731Test

المؤلفون: Yung-Mei Chao, Kay L. H. Wu, Pei-Chia Tsai, You-Lin Tain, Steve Leu, Wei-Chia Lee, Julie Y. H. Chan

المصدر: Journal of Biomedical Science, Vol 27, Iss 1, Pp 1-18 (2020)

مصطلحات موضوعية: Maternal high fructose, AMP-activated protein kinase, Sirtuins, Angiotensin type 1 receptor, Rostral ventrolateral medulla, Programmed hypertension, Medicine

الوصف: Abstract Background Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. Methods Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction. Results Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phox subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension. Conclusion Dysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12929-020-00660-zTest; https://doaj.org/toc/1423-0127Test

الوصول الحر: https://doaj.org/article/ada45c778a214767aff495205233790eTest

المؤلفون: Natalia L. Rukavina Mikusic, Mauro G. Silva, Angélica M. Pineda, Mariela M. Gironacci

المصدر: Frontiers in Pharmacology, Vol 11 (2020)

مصطلحات موضوعية: angiotensin type 1 receptor, angiotensin type 2 receptor, Mas receptor, G-protein–coupled receptor, trafficking, heteromerization, Therapeutics. Pharmacology, RM1-950

الوصف: G-protein–coupled receptors (GPCRs) are targets for around one third of currently approved and clinical prescribed drugs and represent the largest and most structurally diverse family of transmembrane signaling proteins, with almost 1000 members identified in the human genome. Upon agonist stimulation, GPCRs are internalized and trafficked inside the cell: they may be targeted to different organelles, recycled back to the plasma membrane or be degraded. Once inside the cell, the receptors may initiate other signaling pathways leading to different biological responses. GPCRs’ biological function may also be influenced by interaction with other receptors. Thus, the ultimate cellular response may depend not only on the activation of the receptor from the cell membrane, but also from receptor trafficking and/or the interaction with other receptors. This review is focused on angiotensin receptors and how their biological function is influenced by trafficking and interaction with others receptors.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/article/10.3389/fphar.2020.01179/fullTest; https://doaj.org/toc/1663-9812Test

الوصول الحر: https://doaj.org/article/1d257e461b5e47f79b961b9bdb8c5a91Test

المؤلفون: Gold, Annika, Fichtner, Alexander, Choukair, Daniela, Schmitt, Claus Peter, Süsal, Caner, Dragun, Duska, Toenshoff, Burkhard

المصدر: http://lobid.org/resources/99370671682606441Test#!, 36(3):725-729.

مصطلحات موضوعية: What’s New in Renal Transplantation, Kidney transplantation, Kidney/immunology [MeSH], Angiotensin type 1 receptor antibodies, Graft Rejection [MeSH], Humans [MeSH], Antibody-mediated rejection, Kidney Transplantation/adverse effects [MeSH], Receptor, Angiotensin, Type 1 [MeSH], Graft Survival [MeSH], Brief Report, Male [MeSH], HLA Antigens [MeSH], Donor-specific HLA antibodies, Child [MeSH], Antibodies [MeSH], Angiotensin II [MeSH]

الوصف: Background!#!Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT!##!Case!#!We report on a male patient with kidney failure in infancy due to obstructive uropathy who had lost his first kidney transplant due to AT!##!Conclusion!#!This case highlights the difficulty of persistently decreasing elevated AT

العلاقة: https://repository.publisso.de/resource/frl:6467730Test; https://doi.org/10.1007/s00467-020-04879-8Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851028Test/

الإتاحة: https://doi.org/10.1007/s00467-020-04879-8Test
https://repository.publisso.de/resource/frl:6467730Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851028Test/

المؤلفون: Ahmed Elshafei, Emad Gamil Khidr, Maher H. Gomaa, Ahmed A. El-Husseiny

المصدر: Saudi Journal of Biological Sciences, Vol 28, Iss 11, Pp 6465-6470 (2021)
Saudi Journal of Biological Sciences

مصطلحات موضوعية: Coronavirus disease 2019 (COVID-19), QH301-705.5, miR-21, microRNA-21, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ACE2, Review, Disease, CVD, cardiovascular disease, Pharmacology, Lung injury, ACE2, angiotensin-converting enzyme 2, TGF-β, transforming growth factor-beta, ACE1, angiotensin-converting enzyme 1, ACEIs, angiotensin-converting enzyme inhibitors, Ang 1-7, angiotensin 1-7, ERK, extracellular signal-regulated kinase, RAAS, renin-angiotensin-aldosterone system, Fibrosis, Angiotensin 1–7, ARBs, angiotensin receptor blockers, Pulmonary fibrosis, Renin–angiotensin system, medicine, AT2R, angiotensin type 2 receptor, ARBs, Biology (General), COVID-19, coronavirus disease 2019, business.industry, AngII, angiotensin II, NLRP3, (NOD, LRR, and pyrin domain-containing protein 3), Angiotensin II, ACEIs, COVID-19, AngI, angiotensin I, medicine.disease, ICU, intensive care unit, AT1R, angiotensin type 1 receptor, AEC-II, alveolar epithelial type II cells, General Agricultural and Biological Sciences, business, MAPK, mitogen-activated protein kinase, hormones, hormone substitutes, and hormone antagonists, Ang 1-9, angiotensin 1-9

الوصف: The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1–7 (Ang 1–7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::73d5f9b3141b315ed573222f71db5af3Test
http://www.sciencedirect.com/science/article/pii/S1319562X2100574XTest

المؤلفون: Hiroyuki Kawagishi, Mitsuhiko Yamada, Cheng-Kun Du, Tsutomu Nakada, Toshihide Kashihara, Sachio Morimoto, Elena E. Wolf, Shin Kadota, Takuro Numaga-Tomita, Yuji Shiba

المصدر: JACC: Basic to Translational Science

مصطلحات موضوعية: 0301 basic medicine, Inotrope, Agonist, PHF, pediatric heart failure, hiPSC-CM, human induced pluripotent stem cell–derived cardiac myocyte, medicine.drug_class, BBA, β-arrestin–biased angiotensin type 1 receptor agonist, 030204 cardiovascular system & hematology, Pharmacology, 03 medical and health sciences, chemistry.chemical_compound, ECG, electrocardiography, 0302 clinical medicine, ROS, reactive oxygen species, beta-arrestin-biased AT1 angiotensin receptor agonist, Renin–angiotensin system, Heart rate, medicine, OCR, oxygen consumption rate, Aldosterone, Angiotensin II receptor type 1, UCG, ultrasound cardiogram, business.industry, pediatric heart failure, AngII, angiotensin II, medicine.disease, human induced pluripotent stem cell-derived cardiac myocytes, inotropic vasodilator, Angiotensin II, human induced pluripotent stem cell–derived cardiac myocytes, congenital dilated cardiomyopathy, 030104 developmental biology, mNVCM, mouse neonatal ventricular cardiac myocyte, chemistry, β-arrestin–biased AT1 angiotensin receptor agonist, Heart failure, AT1R, angiotensin type 1 receptor, GPCR, G protein–coupled receptor, Preclinical Research, neonate, Cardiology and Cardiovascular Medicine, business, Editorial Comment, LTCC, CaV1.2 L-type Ca2+ channel, TRV027

الوصف: Visual Abstract
Highlights • β-arrestin–biased AT1 agonist TRV027 causes a neonatal-specific, long-acting positive inotropic effect with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. • Although TRV027 stimulates adrenaline secretion, it does not contribute to the inotropic effect. • TRV027 also increases twitch Ca2+ transients in human iPS cell–derived cardiac myocytes bearing immature phenotype and improves the contractility of the compromised heart of neonatal knock-in mice bearing a mutation causing human congenital dilated cardiomyopathy. • TRV027 and related peptides are also known to cause an antiapoptotic effect on the heart, dilate resistant arteries to reduce afterload, and increase Na+ diuresis to reduce preload. • Thus, TRV027 could be utilized as a valuable inotropic vasodilator specific for pediatric heart failure.
Summary The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca2+ channels through angiotensin type 1 receptor (AT1R) and β-arrestin. TRV027, a β-arrestin–biased AT1R agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the AT1R/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the AT1R/β-arrestin/L-type Ca2+ channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1f2d81ed3d68f51843a352e270a974bTest
https://soar-ir.repo.nii.ac.jp/records/2001244Test

المؤلفون: Fang Wu, Hong-Yan Wang, Fan Cai, Ling-Jie Wang, Feng-Ru Zhang, Xiao-Nan Chen, Qian Yang, Meng-Hui Jiang, Xue-Feng Wang, Wei-Feng Shen

المصدر: Chinese Medical Journal, Vol 128, Iss 2, Pp 153-158 (2015)

مصطلحات موضوعية: Angiotensin Type 1 Receptor Antagonist, Elderly, Hypertension, Platelet Activity, Thrombosis, Medicine

الوصف: Background: Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension. Methods: Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA). Results: PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L). Conclusions: AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.

وصف الملف: electronic resource

العلاقة: http://www.cmj.org/article.asp?issn=0366-6999;year=2015;volume=128;issue=2;spage=153;epage=158;aulast=WuTest; https://doaj.org/toc/0366-6999Test

الوصول الحر: https://doaj.org/article/ccfaf78530f4452682c1d97d9f3c2adeTest