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 ß-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of ß-adrenoceptors (ß-ARs). This study aimed to identify a putative target (ß-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 x kg(-1)) and validated by echocardiography and left ventricle (LV) catheterization. The ß-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/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific ß-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, ß3-AR expression was only decreased at d70 (-37±8%). At d35, ß1-AR expression was decreased by 68±6%, but ex vivo ß1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. ß2-AR expression was increased both at d35 (+58±22%) and d70 (+174±35%), with an increase of ex vivo ß2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect ß2-AR response in Dox-CM hearts, suggesting a decoupling of ß2-AR to Gi protein. CONCLUSION: This study highlights the ß1/ß2-AR imbalance in early Dox-CM and reveals the important role that ß2-AR/Gi coupling could play in this pathology. Our results suggest that ß2-AR could be an interesting target at early stage of Dox-CM.