Increased Beta2-Adrenoceptors in Doxorubicin-Induced Cardiomyopathy in Rat

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.