Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Cardiovasc Res. 2011 Feb 1;89(2):309-19. doi: 10.1093/cvr/cvq335. Epub 2010 Oct 25.
Adiponectin (APN) has been reported to protect against ischaemia-reperfusion injury and hypertrophy. However, few reports have investigated the cardioprotective effects of APN in doxorubicin (DOX)-induced cardiomyopathy; therefore, we studied the cardioprotective mechanisms of APN in this model.
In an in vivo study, we quantified the cardiac pathohistology of C57BL/6 mice [wild-type (WT) mice], APN transgenic mice with high APN concentrations [APN transgenic sense (SE) mice], and those with reduced APN concentrations [APN transgenic antisense (AS) mice] after intraperitoneal injections of DOX (4 mg/kg) weekly for 6 weeks. The survival rate after 14 days was significantly increased in APN-SE mice (WT vs. APN-AS vs. APN-SE: 40 vs. 17 vs. 73%, P < 0.05). We assessed myocardial pathohistological changes and observed that fibrosis and apoptosis were significantly decreased in APN-SE mice compared with those of the other groups. We also assessed DOX-induced apoptotic mechanisms in vitro using cultured cardiomyocytes isolated from neonatal WT mice. The expression of adenosine monophosphate-activated protein kinase (AMPK) and anti-apoptotic factor Bcl-2 increased, but that of pro-apoptotic factor Bax decreased in cardiomyocytes treated with highly concentrated APN. The protective effects of APN were reversed by the addition of an AMPK inhibitor (dorsomorphin) to the culture medium.
These data suggest that APN improved cardiac function through anti-apoptotic effects by up-regulation of AMPK in DOX-induced cardiomyopathy in mice.
脂联素 (APN) 已被报道可防止缺血再灌注损伤和肥大。然而，很少有报道研究 APN 在阿霉素 (DOX) 诱导的心肌病中的心脏保护作用；因此，我们在该模型中研究了 APN 的心脏保护机制。
在一项体内研究中，我们对 C57BL/6 小鼠（野生型 (WT) 小鼠）、APN 转基因高浓度 APN 小鼠（APN 转基因感觉 (SE) 小鼠）和 APN 转基因低浓度 APN 小鼠（APN 转基因反义 (AS) 小鼠）的心脏组织病理学进行了量化，这些小鼠在腹腔内注射 DOX（4mg/kg）后每周注射一次，共 6 周。14 天后的存活率在 APN-SE 小鼠中显著增加（WT 与 APN-AS 与 APN-SE：40 与 17 与 73%，P < 0.05）。我们评估了心肌组织病理学变化，发现与其他组相比，APN-SE 小鼠的纤维化和细胞凋亡明显减少。我们还在体外使用从新生 WT 小鼠分离的心肌细胞评估了 DOX 诱导的凋亡机制。在经高浓度 APN 处理的心肌细胞中，腺苷单磷酸激活蛋白激酶 (AMPK) 和抗凋亡因子 Bcl-2 的表达增加，而促凋亡因子 Bax 的表达减少。在培养物中添加 AMPK 抑制剂（dorsomorphin）可逆转 APN 的保护作用。
这些数据表明，APN 通过上调 AMPK 改善了 DOX 诱导的心肌病小鼠的心脏功能，从而发挥抗凋亡作用。
