Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy

Area of Science:

• Cardiology
• Molecular Biology
• Pharmacology

Background:

• Biased agonism of angiotensin II receptor influences cardiac contractility via myofilament changes.
• Dilated cardiomyopathy is characterized by reduced myofilament calcium responsiveness.
• Beta-arrestin signaling is a potential target for improving cardiac function in familial dilated cardiomyopathy.

Purpose of the Study:

• To investigate the effect of beta-arrestin 2-biased angiotensin II receptor agonism on myofilament calcium responsiveness and cardiac function in a mouse model of familial dilated cardiomyopathy.
• To elucidate the signaling mechanisms underlying these effects, focusing on posttranslational modifications and protein interactions.

Main Methods:

• Treatment of a dilated cardiomyopathy mouse model (Tm-E54K) with a beta-arrestin 2-biased ligand (TRV120067) or losartan for 3 months.
• Assessment of cardiac function via echocardiography.
• Analysis of myofilament calcium response in fiber bundles.
• Proteomic analysis for posttranslational modifications.
• Evaluation of signaling pathways in vivo and in isolated myocytes.

Main Results:

• TRV120067 treatment improved cardiac structure and function in Tm-E54K mice, unlike losartan.
• Myofilament calcium responsiveness was significantly enhanced in TRV120067-treated mice.
• Increased phosphorylation of MLC2v and MYPT1/2, mediated by ERK1/2-RSK3 signaling and sarcomere-localized beta-arrestin, was observed.

Conclusions:

• Long-term beta-arrestin 2-biased angiotensin II receptor agonism is a potential therapeutic strategy for dilated cardiomyopathy.
• This approach improves cardiac function by enhancing myofilament calcium responsiveness.
• Beta-arrestin signaling pathways may offer a novel mechanism for treating heart failure.