Watson Peter A, Reusch Jane E B, McCune Sylvia A, Leinwand Leslie A, Luckey Stephen W, Konhilas John P, Brown David A, Chicco Adam J, Sparagna Genevieve C, Long Carlin S, Moore Russell L
University of Colorado Health Sciences Center, and Denver VA Medical Center, 1055 Clermont Street, Denver CO 80220, USA.
Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H246-59. doi: 10.1152/ajpheart.00734.2006. Epub 2007 Mar 2.
Potential regulation of two factors linked to physiological outcomes with left ventricular (LV) hypertrophy, resistance to apoptosis, and matching of metabolic capacity, by the transcription factor cyclic-nucleotide regulatory element binding protein (CREB), was examined in the two models of physiological LV hypertrophy: involuntary treadmill running of female Sprague-Dawley rats and voluntary exercise wheel running in female C57Bl/6 mice. Comparative studies were performed in the models of pathological LV hypertrophy and failure: the spontaneously hypertension heart failure (SHHF) rat and the hypertrophic cardiomyopathy (HCM) transgenic mouse, a model of familial idiopathic cardiomyopathy. Activating CREB serine-133 phosphorylation was decreased early in remodeling in response to both physiological (decreased 50-80%) and pathological (decreased 60-80%) hypertrophic stimuli. Restoration of LV CREB phosphorylation occurred concurrent with completion of physiological hypertrophy (94% of sedentary control), but remained decreased (by 90%) during pathological hypertrophy. In all models of hypertrophy, CREB phosphorylation/activation demonstrated strong positive correlations with 1) expression of the anti-apoptotic protein bcl-2 (a CREB-dependent gene) and subsequent reductions in the activation of caspase 9 and caspase 3; 2) expression of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1; a major regulator of mitochondrial content and respiratory capacity), and 3) LV mitochondrial respiratory rates and mitochondrial protein content. Exercise-induced increases in LV mitochondrial respiratory capacity were commensurate with increases observed in LV mass, as previously reported in the literature. Exercise training of SHHF rats and HCM mice in LV failure improved cardiac phenotype, increased CREB activation (31 and 118%, respectively), increased bcl-2 content, improved apoptotic status, and enhanced PGC-1 content and mitochondrial gene expression. Adenovirus-mediated expression of constitutively active CREB in neonatal rat cardiac recapitulated exercise-induced upregulation of PGC-1 content and mitochondrial oxidative gene expression. These data support a model wherein CREB contributes to physiological hypertrophy by enhancing expression of genes important for efficient oxidative capacity and resistance to apoptosis.
在生理性左心室（LV）肥大的两种模型中，研究了转录因子环磷酸核苷酸调节元件结合蛋白（CREB）对与生理结果相关的两个因素的潜在调节作用，这两个因素分别是抗凋亡能力以及代谢能力的匹配。这两种生理性LV肥大模型分别为：雌性Sprague-Dawley大鼠的非自愿跑步机跑步以及雌性C57Bl/6小鼠的自愿运动轮跑步。同时，在病理性LV肥大和衰竭模型中进行了对比研究，这些模型包括：自发性高血压心力衰竭（SHHF）大鼠和肥厚型心肌病（HCM）转基因小鼠（一种家族性特发性心肌病模型）。在生理性（降低50 - 80%）和病理性（降低60 - 80%）肥大刺激下，重塑早期激活的CREB丝氨酸-133磷酸化水平降低。左心室CREB磷酸化的恢复与生理性肥大的完成同时发生（达到久坐对照组的94%），但在病理性肥大过程中仍保持降低（降低90%）。在所有肥大模型中，CREB磷酸化/激活与以下方面呈现出强正相关：1）抗凋亡蛋白bcl-2（一种CREB依赖性基因）的表达以及随后caspase 9和caspase 3激活的降低；2）过氧化物酶体增殖物激活受体γ共激活因子-1（PGC-1；线粒体含量和呼吸能力的主要调节因子）的表达；3）左心室线粒体呼吸速率和线粒体蛋白含量。如先前文献报道，运动诱导的左心室线粒体呼吸能力增加与左心室质量增加相称。对处于左心室衰竭状态的SHHF大鼠和HCM小鼠进行运动训练可改善心脏表型，增加CREB激活（分别增加31%和118%），增加bcl-2含量，改善凋亡状态，并增强PGC-1含量和线粒体基因表达。腺病毒介导的组成型活性CREB在新生大鼠心脏中的表达重现了运动诱导的PGC-1含量上调和线粒体氧化基因表达上调。这些数据支持了一种模型，即CREB通过增强对有效氧化能力和抗凋亡重要的基因表达来促进生理性肥大。
