Department of Medicine, Rhode Island Hospital, Brown University , Providence, Rhode Island.
Department of Surgery, Boston University Medical School, Roger Williams Medical Center , Providence, Rhode Island.
J Appl Physiol (1985). 2018 Dec 1;125(6):1968-1978. doi: 10.1152/japplphysiol.00006.2018. Epub 2018 Oct 4.
Histone deacetylases (HDACs) play a critical role in modulating cardiac function and ischemic injury. HDAC4 was found to be elevated and activated in response to injury. However, whether HDAC4 mediates cardiac function is currently unknown. In this study, we created myocyte-specific activated HDAC4 transgenic mice to examine the role of HDAC4 in mediating cardiac function during development and response to infarction. There are no differences in cardiac function and gross phenotype between wild-type and cardiomyocyte-specific HDAC4 transgenic mice at 1 mo of age. However, cardiac dysfunction and vascular growth deficiency were displayed in 6-mo-old HDAC4-transgenic mice compared with wild-type mice. Activation of HDAC4 increased heart and myocyte size, hypertrophic proteins, and interstitial fibrosis in 6-mo-old mice but not in 1-mo-old mice. To further define whether activated HDAC4 in the heart could impact myocardial function and remodeling, myocardial infarction was created in both wild-type and cardiomyocyte-specific HDAC4-transgenic mice. In myocardial infarction, the overexpression of activated HDAC4 exacerbated cardiac dysfunction and augmented cardiac remodeling and interstitial fibrosis, which was associated with the reduction of cardiokines in the heart. These results indicate the activation of HDAC4 as a crucial regulator for cardiac function in development and myocardial infarction. NEW & NOTEWORTHY We created myocyte-specific activated HDAC4-transgenic mice to examine the function of HDAC4 in mediating cardiac function. HDAC4 overexpression led to cardiac dysfunction, which was associated with increased hypertrophy and myocardial fibrosis. Furthermore, the overexpression of activated HDAC4 exacerbated cardiac dysfunction, augmented remodeling, and increased apoptosis in the infarcted heart. This is the first demonstration that transgenic overexpression of HDAC4 is crucial for modulation of cardiac function and remodeling.
组蛋白去乙酰化酶 (HDACs) 在调节心脏功能和缺血性损伤中起着关键作用。研究发现，HDAC4 会在受到损伤时升高并被激活。然而，HDAC4 是否介导心脏功能目前尚不清楚。在这项研究中，我们构建了心肌细胞特异性激活的 HDAC4 转基因小鼠，以研究 HDAC4 在介导心脏发育和对梗死的反应中的作用。在 1 月龄时，野生型和心肌细胞特异性 HDAC4 转基因小鼠的心脏功能和大体表型没有差异。然而，与野生型小鼠相比，6 月龄的 HDAC4 转基因小鼠表现出心脏功能障碍和血管生长缺陷。在 6 月龄的小鼠中，HDAC4 的激活增加了心脏和心肌细胞的大小、肥大蛋白和间质纤维化，但在 1 月龄的小鼠中没有。为了进一步确定心脏中激活的 HDAC4 是否会影响心肌功能和重塑，我们在野生型和心肌细胞特异性 HDAC4 转基因小鼠中创建了心肌梗死模型。在心肌梗死后，激活的 HDAC4 的过表达加剧了心脏功能障碍，并增强了心脏重塑和间质纤维化，这与心脏中心肌细胞因子的减少有关。这些结果表明，HDAC4 的激活是心脏在发育和心肌梗死过程中调节心脏功能的关键调节因子。本研究的创新之处在于构建了心肌细胞特异性激活的 HDAC4 转基因小鼠，以研究 HDAC4 在介导心脏功能中的作用。HDAC4 的过表达导致心脏功能障碍，这与心肌肥大和纤维化增加有关。此外，激活的 HDAC4 的过表达加剧了梗死心脏的心脏功能障碍、重塑和凋亡。这是首次证明 HDAC4 的转基因过表达对于调节心脏功能和重塑至关重要。
