Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, New York;
Am J Physiol Heart Circ Physiol. 2013 Sep 15;305(6):H875-84. doi: 10.1152/ajpheart.00342.2013. Epub 2013 Jul 5.
Mammalian enabled (Mena) is a key regulator of cytoskeletal actin dynamics, which has been implicated in heart failure (HF). We have previously demonstrated that cardiac Mena deletion produced cardiac dysfunction with conduction abnormalities and hypertrophy. Moreover, elevated Mena expression correlates with HF in human and animal models, yet the precise role of Mena in cardiac pathophysiology is unclear. In these studies, we evaluated mice with cardiac myocyte-specific Mena overexpression (TTA/TgTetMena) comparable to that observed in cardiac pathology. We found that the hearts of TTA/TgTetMena mice were functionally and morphologically comparable to wild-type littermates, except for mildly increased heart mass in the transgenic mice. Interestingly, TTA/TgTetMena mice were particularly susceptible to cardiac injury, as these animals experienced pronounced decreases in ejection fraction and fractional shortening as well as heart dilatation and hypertrophy after transverse aortic constriction (TAC). By "turning off" Mena overexpression in TTA/TgTetMena mice either immediately prior to or immediately after TAC surgery, we discovered that normalizing Mena levels eliminated cardiac hypertrophy in TTA/TgTetMena animals but did not preclude post-TAC cardiac functional deterioration. These findings indicate that hearts with increased levels of Mena fare worse when subjected to cardiac injury and suggest that Mena contributes to HF pathophysiology.
哺乳动物效应物（Mena）是细胞骨架肌动蛋白动力学的关键调节因子，它与心力衰竭（HF）有关。我们之前已经证明，心脏 Mena 缺失会导致心脏功能障碍、传导异常和肥大。此外，Mena 表达水平升高与人类和动物模型中的 HF 相关，但 Mena 在心脏病理生理学中的确切作用尚不清楚。在这些研究中，我们评估了心肌细胞特异性过表达 Mena（TTA/TgTetMena）的小鼠，其表达水平与心脏病理学中观察到的相似。我们发现，TTA/TgTetMena 小鼠的心脏在功能和形态上与野生型同窝仔鼠相似，除了转基因小鼠的心脏质量略有增加。有趣的是，TTA/TgTetMena 小鼠特别容易受到心脏损伤，因为这些动物在横主动脉缩窄（TAC）后，射血分数和缩短分数明显降低，以及心脏扩张和肥大。通过在 TAC 手术之前或之后立即“关闭”TTA/TgTetMena 小鼠中的 Mena 过表达，我们发现，使 Mena 水平正常化消除了 TTA/TgTetMena 动物的心脏肥大，但并未排除 TAC 后的心脏功能恶化。这些发现表明，心脏中 Mena 水平升高时，在受到心脏损伤时会表现更差，并表明 Mena 有助于 HF 病理生理学。
