阿霉素的心肌毒性限制了其作为廉价、高效、广谱的抗肿瘤药物的临床应用，如何有效预防阿霉素心肌病具有重要的临床意义。我们此前研究发现：衰竭的心肌组织中1型磷酸酶（PP1）活性增强，持续过表达PP1有活性的内源性抑制因子-1基因片段（I-1c：T35D,1-65AA）可抑制PP1活性，降低肌浆网钙循环调节蛋白Phospholamban的磷酸化水平及抑制心肌细胞凋亡，从而减轻了缺血性心肌病动物模型中缺血再灌注损伤和心功能恶化。目前尚不清楚，I-1c能否保护阿霉素所致的心肌病。本研究基于我们此前建立的有活性的I-1c基因片段过度表达小鼠和全长I-1基因敲除小鼠模型，结合以重组腺相关病毒AAV9.I-1c对阿霉素心肌病大鼠的基因治疗方法，探讨通过激活I-1，抑制PP1活性，能否有效预防阿霉素诱导的心力衰竭及其潜在的分子病理机制。为临床防治阿霉素所致心肌病和心力衰竭提供新的治疗靶标和策略。

The anticancer efficacy of Doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity resulting in heart failure. Therefore, effective preventive measures are preferable. Cardiomyocyte necrotic and apoptotic loss，as well as impaired sarcoplamic reticulum (SR) Ca-pump function and abnormal Ca-cycling, key characteristics of heart failure , are partially attributable to dephosphorylation of phospholamban (PLN) by increased protein phosphatase 1 (PP1) activity. Recently, we found that overexpression of active Inhibitor-1, an endogenous inhibitor of PP1, enhanced cardiac Ca-cycling and contractility as well as protected from cardiomyocyte necrosis and apoptosis associated with pressure-overload, ischemia/reperfusion injury, and prolonged β-adrenergic stimulation. However, it is not clear whether activation of inhibitor-1 would exert similar protective effects against Dox-induced cardiac injury. To delineate the cardioprotection of constitutively active (T35D, AA 1–65) Inhibitor-1 (I-1c) against Dox-induced cardiotoxicity, I-1c was up-regulated by ex vivo adenovirus-mediated gene delivery in isolated adult rat cardiomyocytes, and in vivo transgenic mice with cardiac specific overexpression of I-1c or full-length I-1 deficiency , subjecting to acute and chronic Dox treatment. Furthermore, in the present study, we will use AAV9-mediated gene delivery systerm to investigate whether in vivo acute gene transfer of I-1c could improve hemodynamics in the setting of preexisting Dox-induced heart failure. This is the first study to elucidate: 1) activation of I-1 protects against Dox-induced acute and chronic cardiac injury both ex vivo and in vivo; 2) the cardioprotection of I-1c is associated with the specific interactions between I-1c and its molecular targets in both mitochondria-mediated and ER stress-mediated cardiomyocyte survival and/or apoptosis pathways; 3) The cardioprotection of I-1c is associated with phosphorylated PLN-related calcium homeostasis; 4) acute increases of I-1c in preexisting intact failing heart could result in improved function and attenuated cardiac remodeling. These studies will, for the first time, provide a detail mechanism of Inhitor-1’s cardioprotection against Dox-triggered cardiac injury at subcellular and moleclular levels, indicating activation of inhibitor-1 of PP1 may hold promise as an attractive new therapeutic target in heart failure.