β-Arrestin-Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate
| العنوان: | β-Arrestin-Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate |
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| 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 |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| 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 |
| اللغة: | English |
| تدمد: | 2452-302X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1f2d81ed3d68f51843a352e270a974bTest https://soar-ir.repo.nii.ac.jp/records/2001244Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d1f2d81ed3d68f51843a352e270a974b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2452302X |
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