التفاصيل البيبلوغرافية
| العنوان: |
Abstract MP257: Dual Actions Of β 2 Ar-agonism Confer Protection Against Heart Failure And Renal Dysfunction Via Inotropic And Lusitropic Effects And Normalized Cholesterol Homeostasis In A Mouse Model Of Alport Syndrome |
| المؤلفون: |
Chahdi, Ahmed, Yousefi, Keyvan, Condor Capcha, Jose Manuel, Irion, Camila, Lambert, Guerline, Shehadeh, Serene, Dunkley, Julian, Lee, Yee-Shuan, Khan, Aisha, Ramic, Melina, Andrade, Nadja, Zeier, Zane, Dykxhoorn, Derek, Katsoufis, Chryso, freundlich, michael, Hare, Joshua M, Nabity, Mary, Rivera, Carolina, Lymperopoulos, Anastasios, Webster, Keith A, Zelcer, Noam, Shehadeh, Lina A |
| المصدر: |
Circulation Research ; volume 129, issue Suppl_1 ; ISSN 0009-7330 1524-4571 |
| بيانات النشر: |
Ovid Technologies (Wolters Kluwer Health) |
| سنة النشر: |
2021 |
| الوصف: |
Background: Col4a3 -/- Alport mice present a model of heart failure with preserved ejection fraction (HFpEF) secondary to chronic kidney disease (CKD) wherein etiological relationships have been established between hypertension, pulmonary edema, inflammation, cardiac hypertrophy and fibrosis, diastolic dysfunction and underlying abnormalities of elevated low-density lipoprotein receptor (LDLR) expression, excess LDL-cholesterol (LDL-C) accumulation, and mitochondrial dysfunction in renal tubules. HFpEF is characteristically unresponsive to pharmacological intervention. Here, we tested the hypothesis that selective β 2 -Adrenoceptor (β 2 AR) modulation with salbutamol, a short-acting β 2 AR agonist, could alleviate symptoms of CKD and simultaneously augment cardiac function. Secondarily, we investigated the mechanism of actions of such β 2 AR-mediated therapeutics on cardiac and renal functions. Methods: Alport mice were injected intraperitoneally with salbutamol or DMSO vehicle as a single bolus of 200μg/dose in short-term studies or daily with 100 μg/dose for 2 weeks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection. In vitro mechanistic studies were performed in HK-2, Alport dog smooth muscle and tubular epithelial cells differentiated from Alport patient-derived iPSCs. Protein-protein interactions were studied using co-immunoprecipitation experiments and LDL-C uptake was measured by live-cell imaging. Results: Short-term, salbutamol improved renal function in parallel with decreased LDLR levels and reduced uptake of LDL-C into renal tubules. Long-term, cardiac diastolic function assessed by isovolumetric relaxation time (IVRT), filling pressures (E/E’), and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP. Mechanistically, in the kidney, salbutamol activated IDOL and hence lysosomal ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1161/res.129.suppl_1.mp257 |
| الإتاحة: |
https://doi.org/10.1161/res.129.suppl_1.mp257Test |
| رقم الانضمام: |
edsbas.CB323AF6 |
| قاعدة البيانات: |
BASE |
