β-Arrestin-Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate
| Autor: | Hiroyuki Kawagishi, Mitsuhiko Yamada, Cheng-Kun Du, Tsutomu Nakada, Toshihide Kashihara, Sachio Morimoto, Elena E. Wolf, Shin Kadota, Takuro Numaga-Tomita, Yuji Shiba |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | JACC: Basic to Translational Science |
| ISSN: | 2452-302X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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