Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway.
Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway.
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DOI：
10.1161/circulationaha.112.001212
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发表时间：
2013-04-23
期刊：
影响因子：
37.8
通讯作者：
Vatner DE
中科院分区：
文献类型：
--
作者：
Lai L;Yan L;Gao S;Hu CL;Ge H;Davidow A;Park M;Bravo C;Iwatsubo K;Ishikawa Y;Auwerx J;Sinclair DA;Vatner SF;Vatner DE
由于尚不清楚的原因，5 型 AC (AC5)（心脏中两种主要的 AC 亚型之一）对于心脏应激反应是否具有保护性或有害性尚存在争议。为了调和这一争议，我们研究了 AC5 转基因 (Tg) 小鼠中慢性异丙肾上腺素 (ISO) 诱导的心肌病及其相关信号传导机制。慢性 ISO 增加了氧化应激，并在 AC5 Tg 中诱发更严重的心肌病，因为左心室 (LV) 射血分数比野生型 (WT) 下降了 1.9 倍，同时 LV 扩张更大，纤维化、细胞凋亡和肥大增加。 8-OhDG 检测到，AC5 Tg 心脏中慢性 ISO 诱导的氧化应激增加了 15%（p=0.007），而 MnSOD 蛋白表达降低了 38%，表明 AC5 Tg 心肌病的易感性可能是由于 MnSOD 表达降低所致。与此一致的是，AC5 Tg 对心肌病的易感性被 MnSOD 的过度表达所抑制，而 AC5 KO 提供的保护在 AC5 KO×MnSOD+/- 小鼠中丧失。 Sirtuin 和 MEK 抑制剂均消除了 MnSOD 的升高，表明 SIRT1/FoxO3a 和 MEK/ERK 通路均参与 AC5 对 MnSOD 的调节。 AC5 的过度表达通过改变 SIRT1/FoxO3a、MEK/ERK 和 MnSOD 的调节，导致氧化应激不耐受，从而加剧慢性儿茶酚胺应激诱导的心肌病，从而为治疗心力衰竭的新方法提供了线索。
For reasons that remain unclear, whether type 5 AC (AC5), one of two major AC isoforms in heart, is protective or deleterious in response to cardiac stress is controversial. To reconcile this controversy we examined the cardiomyopathy induced by chronic isoproterenol (ISO) in AC5 transgenic (Tg) mice and the signaling mechanisms involved. Chronic ISO increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular (LV) ejection fraction fell 1.9 fold more than wild type (WT), along with greater LV dilation and increased fibrosis, apoptosis and hypertrophy. Oxidative stress induced by chronic ISO, detected by 8-OhDG was 15% greater, p=0.007, in AC5 Tg hearts, while protein expression of MnSOD was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be due to decreased MnSOD expression. Consistent with this, susceptibility of the AC5 Tg to cardiomyopathy was suppressed by overexpression of MnSOD, whereas protection afforded by the AC5 KO was lost in AC5 KO×MnSOD+/− mice. Elevation of MnSOD was eliminated by both sirtuin and MEK inhibitors, suggesting both the SIRT1/FoxO3a and MEK/ERK pathway are involved in MnSOD regulation by AC5. Overexpression of AC5 exacerbates the cardiomyopathy induced by chronic catecholamine stress by altering regulation of SIRT1/FoxO3a, MEK/ERK and MnSOD, resulting in oxidative stress intolerance, thereby shedding light on new approaches for treatment of heart failure.