Thyroid hormone (T3) plus dual-specificity phosphatase-5 siRNA therapy regenerates the myocardium lost as a result of doxorubicin cardiotoxicity

Abstract

Doxorubicin is a widely used antineoplastic drug. However, its major side effect, cardiotoxicity, results from cardiomyocyte loss that causes left ventricle (LV) wall thinning, chronic LV dysfunction and heart failure. Here, we show that transient therapy with thyroid hormone (triiodothyronine, T3) and dual-specificity phosphatase-5 (DUSP5) siRNA results in cardiomyocyte proliferation. siRNA-directed depletion of DUSP5, a nuclear localized p-ERK1/2-specific phosphatase, sensitizes cardiomyocytes to the proliferative effects of T3 by potentiating p-ERK1/2 accumulation resulting from the activation of T3-mediated insulin-like growth factor-1 (IGF-1) signaling. In mice with chronic doxorubicin cardiotoxicity, this therapy regenerates the LV myocardium by cardiomyocyte proliferation, reverses LV dysfunction and prevents progressive chamber dilatation, providing a strategy for addressing a currently untreatable condition.