Abstract 12089: Dual Actions of β2AR-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

• Published in: Circulation (New York, N.Y.) N.Y.), 2021-11, Vol.144 (Suppl_1), p.A12089-A12089
• Main Authors: CHAHDI, AHMED, Yousefi, Keyvan, Condor Capcha, Jose Manuel, Irion, Camila, Lambert, Guerline, Shehadeh, Serene A, 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
• Format: Article
• Language: English
• ISSN: 0009-7322
• DOI: 10.1161/circ.144.suppl_1.12089

IntroductionCol4a3-/- 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. HypothesisWe tested the hypothesis that selective β2-Adrenoceptor (β2AR) modulation with salbutamol, a short-acting β2AR agonist, could alleviate symptoms of CKD and simultaneously augment cardiac function. MethodsAlport mice were injected i.p.with salbutamol or DMSO vehicle as a single bolus of 200μg/dose in short-term studies or daily with 100 μg/dose for 2 wks long-term. Cardiac and renal functions, cAMP levels, in vivo renal tubular LDL-C uptake and renal histology were evaluated post-injection. N=3-8 for all experiments. ResultsShort-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, filling pressures, and myocardial performance index, and systolic function reflected by ejection fraction, stroke volume and cardiac output improved significantly in parallel with increased cardiac cAMP (p