Senolytic Agent Navitoclax Inhibits Angiotensin II-Induced Heart Failure in Mice

Area of Science:

• Cardiovascular Research
• Cellular Biology
• Pharmacology

Background:

• Heart failure with reduced ejection fraction (HFrEF) remains a significant health concern.
• Senescent cells accumulate in the aging heart and contribute to cardiac dysfunction.
• Current treatments for HFrEF have limitations, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the therapeutic efficacy of navitoclax, a senolytic drug, in a mouse model of angiotensin II (Ang II)-induced heart failure.
• To assess the impact of navitoclax on cardiac function, electrophysiology, and cardiac remodeling.
• To elucidate the cellular mechanisms underlying navitoclax's effects, particularly its impact on senescent cells.

Main Methods:

• Angiotensin II infusion was used to induce heart failure in mice.
• Navitoclax or vehicle was administered to assess its effects on cardiac function via echocardiography and electrophysiological testing.
• Cardiac tissues were analyzed for fibrosis, hypertrophy, and inflammation using histopathological staining, immunofluorescence, and western blotting.
• In vitro studies on isolated cardiomyocytes and cardiac fibroblasts were performed to validate cellular effects.

Main Results:

• Navitoclax significantly improved left ventricular ejection fraction and cardiac function in mice with Ang II-induced heart failure.
• Electrophysiological testing revealed that navitoclax increased conduction velocity and decreased susceptibility to ventricular tachyarrhythmia.
• Histological and molecular analyses demonstrated that navitoclax ameliorated cardiac fibrosis, hypertrophy, and inflammatory responses.
• Navitoclax induced apoptosis in senescent cells, confirming its senolytic activity.

Conclusions:

• Navitoclax demonstrates significant therapeutic potential for treating heart failure with reduced ejection fraction.
• Pharmacological clearance of senescent cells using senolytic drugs like navitoclax represents a promising therapeutic strategy for HFrEF.
• Targeting senescent cells may offer a novel approach to mitigate cardiac fibrosis, hypertrophy, and inflammation in heart failure.