Department of Cell Biology & Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
Circulation. 2013 Apr 23;127(16):1692-701. doi: 10.1161/CIRCULATIONAHA.112.001212. Epub 2013 Mar 27.
For reasons that remain unclear, whether type 5 adenylyl cyclase (AC5), 1 of 2 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 in AC5 transgenic (Tg) mice and the signaling mechanisms involved.
Chronic isoproterenol increased oxidative stress and induced more severe cardiomyopathy in AC5 Tg, as left ventricular ejection fraction fell 1.9-fold more than wild type, along with greater left ventricular dilation and increased fibrosis, apoptosis, and hypertrophy. Oxidative stress induced by chronic isoproterenol, detected by 8-OhDG was 15% greater, P=0.007, in AC5 Tg hearts, whereas protein expression of manganese superoxide dismutase (MnSOD) was reduced by 38%, indicating that the susceptibility of AC5 Tg to cardiomyopathy may be attributable 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 knockout (KO) was lost in AC5 KO×MnSOD heterozyous KO 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.
目前仍不清楚的是，心脏中两种主要的腺苷酸环化酶（AC）同工酶之一的 5 型 AC（AC5）在应对心脏应激时是具有保护作用还是有害作用，这存在争议。为了解决这一争议，我们研究了慢性异丙肾上腺素在 AC5 转基因（Tg）小鼠中诱导的心肌病及其涉及的信号转导机制。
慢性异丙肾上腺素增加了氧化应激，并在 AC5 Tg 中诱导了更严重的心肌病，左心室射血分数下降了 1.9 倍，左心室扩张更大，纤维化、凋亡和肥大增加。通过 8-OhDG 检测到的慢性异丙肾上腺素诱导的氧化应激在 AC5 Tg 心脏中增加了 15%，P=0.007，而锰超氧化物歧化酶（MnSOD）的蛋白表达减少了 38%，这表明 AC5 Tg 对心肌病的易感性可能归因于 MnSOD 表达的减少。与此一致的是，AC5 Tg 对心肌病的易感性通过 MnSOD 的过表达而受到抑制，而 AC5 敲除（KO）的保护作用在 AC5 KO×MnSOD 杂合 KO 小鼠中丧失。Sirtuin 和 MEK 抑制剂均消除了 MnSOD 的升高，这表明 SIRT1/FoxO3a 和 MEK/ERK 途径均参与了 AC5 对 MnSOD 的调节。
AC5 的过表达通过改变 SIRT1/FoxO3a、MEK/ERK 和 MnSOD 的调节，加剧了慢性儿茶酚胺应激引起的心肌病，导致氧化应激不耐受，从而为心力衰竭的治疗提供了新的方法。
