Pasipoularides Ares
Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA,
J Cardiovasc Transl Res. 2015 Jul;8(5):293-318. doi: 10.1007/s12265-015-9630-8. Epub 2015 May 14.
Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. A primary goal of translational cardiovascular research is recognizing whether disease-related changes in phenotype can be averted by eliminating or reducing the effects of environmental epigenetic risks. There may be significant medical benefits in using gene-by-environment interaction knowledge to prevent or reverse organ abnormalities and disease. This survey proposes that "environmental" forces associated with diastolic RV/LV rotatory flows exert important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations. Mechanisms analogous to Murray's law of hydrodynamic shear-induced endothelial cell modulation of vascular geometry are likely to link diastolic vortex-associated shear, torque and "squeeze" forces to RV/LV adaptations. The time has come to explore a new paradigm in which such forces play a fundamental epigenetic role, and to work out how heart cells react to them. Findings from various imaging modalities, computational fluid dynamics, molecular cell biology and cytomechanics are considered. The following are examined, among others: structural dynamics of myocardial cells (endocardium, cardiomyocytes, and fibroblasts), cytoskeleton, nucleoskeleton, and extracellular matrix; mechanotransduction and signaling; and mechanical epigenetic influences on genetic expression. To help integrate and focus relevant pluridisciplinary research, rotatory RV/LV filling flow is placed within a working context that has a cytomechanics perspective. This new frontier in cardiac research should uncover versatile mechanistic insights linking filling vortex patterns and attendant forces to variable expressions of gene regulation in RV/LV myocardium. In due course, it should reveal intrinsic homeostatic arrangements that support ventricular myocardial function and adaptability.
表观遗传机制在心脏适应、重塑、逆向重塑和疾病过程中起着基础性作用。转化心血管研究的一个主要目标是确定是否可以通过消除或减少环境表观遗传风险的影响来避免与疾病相关的表型变化。利用基因与环境相互作用的知识来预防或逆转器官异常和疾病可能会带来重大的医学益处。本综述提出，与舒张期右心室/左心室旋转血流相关的“环境”力量发挥着重要的表观遗传作用，尽管这种作用仍未得到充分认识，它会影响心脏的功能和形态适应。类似于默里定律中流体动力剪切诱导血管几何形状的内皮细胞调节机制，可能将舒张期涡流相关的剪切力、扭矩和“挤压”力与右心室/左心室的适应联系起来。现在是时候探索一种新的范式了，在这种范式中，这些力量发挥着基本的表观遗传作用，并弄清楚心脏细胞对它们的反应。本文考虑了来自各种成像方式、计算流体动力学、分子细胞生物学和细胞力学的研究结果。除其他外，还研究了以下内容：心肌细胞（心内膜、心肌细胞和成纤维细胞）、细胞骨架、核骨架和细胞外基质的结构动力学；机械转导和信号传导；以及机械表观遗传对基因表达的影响。为了帮助整合和聚焦相关的多学科研究，将右心室/左心室旋转充盈血流置于一个具有细胞力学视角的工作背景中。心脏研究的这一新领域应该揭示将充盈涡流模式和伴随的力量与右心室/左心室心肌基因调控的可变表达联系起来的通用机制见解。在适当的时候，它应该揭示支持心室心肌功能和适应性的内在稳态机制。
