Testosterone Antagonizes Doxorubicin-Induced Senescence of Cardiomyocytes.
Testosterone Antagonizes Doxorubicin-Induced Senescence of Cardiomyocytes.
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DOI：
10.1161/jaha.115.002383
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发表时间：
2016-01-08
影响因子：
5.4
通讯作者：
Ameri P
中科院分区：
文献类型：
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作者：
Altieri P;Barisione C;Lazzarini E;Garuti A;Bezante GP;Canepa M;Spallarossa P;Tocchetti CG;Bollini S;Brunelli C;Ameri P
在青春期和青春期接受多柔比星和其他蒽环类药物治疗的男性患者中，慢性心脏毒性的发生率低于女性。我们假设这种性别差异可能继发于性激素对心肌细胞衰老的不同活性，这被认为是长期蒽环类心肌病发展的核心。将H9 c2细胞和新生小鼠心肌细胞暴露于多柔比星，预先分别与睾酮或17β-雌二醇（主要雄激素和雌激素）孵育或不孵育。替吉奥（而非17β-雌二醇）可抵消阿霉素引起的衰老。端粒结合因子2的下调，以前被认为是阿霉素诱导衰老的关键，也被睾酮阻止，p53磷酸化和积累也是如此。用雄激素受体拮抗剂氟替卡松、磷脂酰肌醇3激酶抑制剂LY 294002和一氧化氮合酶抑制剂L-NG-硝基精氨酸甲酯预处理可消除睾酮所达到的衰老减少和端粒结合因子2水平正常化。同时，睾酮增强AKT和一氧化氮合酶3的磷酸化。在H9 c2细胞中，多柔比星刺激的衰老在处理后长达21天仍然观察到，并且当细胞在首次暴露后14天用多柔比星再激发以模拟含蒽环类化疗的时间表时进一步增加。值得注意的是，这些作用也被睾酮抑制。替吉奥保护心肌细胞免受多柔比星引起的衰老，至少部分是通过调节端粒结合因子2通过一个途径，涉及雄激素受体，磷脂酰肌醇3激酶，AKT，和一氧化氮合酶3。这是青春期和青春期男孩比女孩更不容易发生慢性蒽环类药物心脏毒性的潜在机制。
Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long‐term anthracycline cardiomyopathy. H9c2 cells and neonatal mouse cardiomyocytes were exposed to doxorubicin with or without prior incubation with testosterone or 17β‐estradiol, the main androgen and estrogen, respectively. Testosterone, but not 17β‐estradiol, counteracted doxorubicin‐elicited senescence. Downregulation of telomere binding factor 2, which has been pinpointed previously as being pivotal to doxorubicin‐induced senescence, was also prevented by testosterone, as were p53 phosphorylation and accumulation. Pretreatment with the androgen receptor antagonist flutamide, the phosphatidylinositol 3 kinase inhibitor LY294002, and the nitric oxide synthase inhibitor L‐NG‐nitroarginine methyl ester abrogated the reduction in senescence and the normalization of telomere binding factor 2 levels attained by testosterone. Consistently, testosterone enhanced the phosphorylation of AKT and nitric oxide synthase 3. In H9c2 cells, doxorubicin‐stimulated senescence was still observed up to 21 days after treatment and increased further when cells were rechallenged with doxorubicin 14 days after the first exposure to mimic the schedule of anthracycline‐containing chemotherapy. Remarkably, these effects were also inhibited by testosterone. Testosterone protects cardiomyocytes against senescence caused by doxorubicin at least in part by modulating telomere binding factor 2 via a pathway involving the androgen receptor, phosphatidylinositol 3 kinase, AKT, and nitric oxide synthase 3. This is a potential mechanism by which pubescent and adolescent boys are less prone to chronic anthracycline cardiotoxicity than girls.