School of Medicine, Health Sciences Center, University of Colorado, Denver, Colorado 80045, USA.
Am J Physiol Heart Circ Physiol. 2010 Dec;299(6):H2056-68. doi: 10.1152/ajpheart.00394.2010. Epub 2010 Oct 8.
Cardiac failure is associated with diminished activation of the transcription factor cyclic nucleotide regulatory element binding-protein (CREB), and heart-specific expression of a phosphorylation-deficient CREB mutant in transgenic mice [dominant negative CREB (dnCREB) mice] recapitulates the contractile phenotypes of cardiac failure (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heart. J Clin Invest 101: 2415-2426, 1998). In the present study, we demonstrated significantly elevated mortality and contractile dysfunction in female compared with male dnCREB mice. Female dnCREB mice demonstrated a 21-wk survival of only 17% compared with 67% in males (P < 0.05) and exclusively manifest decreased cardiac peroxisome proliferator-activated receptor-γ coactivator-1α and estrogen-related receptor-α content, suggesting sex-related effects on cardiac mitochondrial function. Hearts from 4-wk-old dnCREB mice of both sexes demonstrated diminished mitochondrial respiratory capacity compared with nontransgenic controls. However, by 12 wk of age, there was a significant decrease in mitochondrial density (citrate synthase activity) and deterioration of mitochondrial structure, as demonstrated by transmission electron microscopy, in female dnCREB mice, which were not found in male transgenic littermates. Subsarcolemmal mitochondria isolated from hearts of female, but not male, dnCREB mice demonstrated increased ROS accompanied by decreases in the expression/activity of the mitochondrial antioxidants MnSOD and glutathione peroxidase. These results demonstrate that heart-specific dnCREB expression results in mitochondrial respiratory dysfunction in both sexes; however, increased oxidant burden, reduced antioxidant expression, and disrupted mitochondrial structure are exacerbated by the female sex, preceding and contributing to the greater contractile morbidity and mortality. These results provide further support for the role of the CREB transcription factor in regulating mitochondrial integrity and identify a critical pathway that may contribute to sex differences in heart failure.
心力衰竭与转录因子环核苷酸调节元件结合蛋白 (CREB) 的激活减少有关，而在转基因小鼠中表达磷酸化缺陷型 CREB 突变体（显性负 CREB (dnCREB) 小鼠）可重现心力衰竭的收缩表型 (Fentzke RC, Korcarz CE, Lang RM, Lin H, Leiden JM. 心脏中表达显性负 CREB 转录因子的转基因小鼠的扩张型心肌病。J Clin Invest 101: 2415-2426, 1998)。在本研究中，我们发现与雄性 dnCREB 小鼠相比，雌性 dnCREB 小鼠的死亡率和收缩功能障碍显著升高。与雄性 dnCREB 小鼠相比，雌性 dnCREB 小鼠的存活率仅为 17%（P < 0.05），且仅表现出心脏过氧化物酶体增殖物激活受体-γ共激活因子-1α和雌激素相关受体-α含量降低，表明心脏线粒体功能存在性别相关影响。与非转基因对照组相比，4 周龄时雌雄 dnCREB 小鼠的心脏均表现出线粒体呼吸能力降低。然而，到 12 周龄时，雌性 dnCREB 小鼠的线粒体密度（柠檬酸合酶活性）显著降低，线粒体结构恶化，透射电镜显示，而雄性转基因同窝仔鼠中则没有发现这种情况。从雌性而非雄性 dnCREB 小鼠的心脏分离出的亚肌节线粒体表现出 ROS 增加，同时线粒体抗氧化剂 MnSOD 和谷胱甘肽过氧化物酶的表达/活性降低。这些结果表明，心脏特异性 dnCREB 表达导致两性的线粒体呼吸功能障碍；然而，雌性动物的氧化应激负担增加、抗氧化剂表达减少和线粒体结构破坏加剧，导致更大的收缩发病率和死亡率。这些结果进一步支持 CREB 转录因子在调节线粒体完整性中的作用，并确定了一个可能导致心力衰竭中性别差异的关键途径。
