ApoM Activates Autophagy and Suppresses Lyosomal Lethargy to Combat Doxorubicin Cardiomyopathy.
ApoM Activates Autophagy and Suppresses Lyosomal Lethargy to Combat Doxorubicin Cardiomyopathy.
复制标题
ApoM 激活自噬并抑制溶酶体嗜睡，以对抗阿霉素心肌病。
DOI：
10.1016/j.jacbts.2022.10.003
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Prins,KurtW
中科院分区：
文献类型：
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作者：
Kazmirczak,Felipe;Prins,KurtW
Doxorubicin and other anthracyclines are used to treat multiple types of cancer, including breast cancer, leukemia, lymphoma, and sarcomas. 1 However, the potential cardiotoxic effects of anthracyclines limits their use clinically, especially in children, in whom anthracycline-based chemotherapy is frequently used. Although anthracycline-induced heart failure is observed in only a minority of patients exposed to anthracyclines, patients with anthracycline cardiomyopathy have poor long-term survival, with mortality rates that match those of patients with idiopathic cardiomyopathy. 1 To more effectively combat anthracycline cardiotoxicity, new approaches aimed at prevention, rather than treating the resultant heart failure, are needed. Because anthracyclines are and will very likely continue to be frontline therapies for multiple types of malignancies, combating anthracycline cardiotoxicity has potential for significant clinical impact in this population. A promising approach is targeting the unique molecular mediators of doxorubicin cardiomyopathy either before or during doxorubicin exposure. Excellent work from several laboratories has nominated multiple mechanisms of doxorubicin cardiomyopathy, which include DNA damage, alteration of myocardial iron handling and resultant induction of ferroptosis, and lysosomal injury. 2 Thus, therapies targeting these specific pathways could hopefully prevent or lessen the likelihood of severe doxorubicin cardiomyopathy, possibly translating into better survival outcomes. Autophagy is an active area of investigation for several distinct cardiovascular diseases, and multiple lines of evidence show that modulation of autophagy has therapeutic effects. 2 Autophagy is the process of protein and organelle breakdown for the regeneration of amino acids, nucleic acids, lipids, and carbohydrates; this crucial activity is orchestrated by lysosomes. Not surprisingly, autophagy is a tightly regulated process, as numerous inputs including signaling molecules and transcription factors affect autophagic flux. First, the nutrient sensing mammalian target of rapamycin (mTOR) pathway is widely thought to be an inhibitor of autophagy, while the adenosine monophosphate–activated protein kinase (AMPK) pathway serves as an autophagy activator. 3 These 2 signaling molecules exhibit significant crosstalk with regard to autophagy induction and flux, and thus proper balancing of their activity is crucial for regulation of autophagy. In addition, transcription factor EB (TFEB) induces expression of genes harboring the coordinated lysosomal expression and regulation motif, and thus TFEB is a transcriptional inducer of autophagy. 3 Because autophagy modulates doxorubicin cardiomyopathy, 2 novel pharmacologic approaches targeting autophagy to combat doxorubicin cardiomyopathy are of particular relevance for this vexing clinical problem. In a study reported in this issue of JACC: Basic to Translational Science, Guo et al 4 investigated the hypothesis that apolipoprotein M (ApoM) modulates doxorubicin cardiomyopathy through its ability to activate autophagy and combat lysosomal injury. In this study, the investigators implemented multiple mechanistic and translational approaches, including
