Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

Abstract

Background

The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of β-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of β-adrenoceptors (β-ARs). This study aimed to identify a putative target (β-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model.

Methodology

Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg.kg ⁻¹) and validated by echocardiography and left ventricle (LV) catheterization. The β-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dt _max, dP/dt _min) was evaluated on isolated heart in response to specific β-AR stimulations at d35.

Results

At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, β ₃-AR expression was only decreased at d70 (-37±8%). At d35, β ₁-AR expression was decreased by 68±6%, but ex vivo β ₁-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. β ₂-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo β ₂-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect β ₂-AR response in Dox-CM hearts, suggesting a decoupling of β ₂-AR to Gi protein.

Conclusion

This study highlights the β ₁/β ₂-AR imbalance in early Dox-CM and reveals the important role that β ₂-AR/Gi coupling could play in this pathology. Our results suggest that β ₂-AR could be an interesting target at early stage of Dox-CM.