Pinto Thaís Silva, Feltran Geórgia da Silva, Fernandes Célio Júnior da C, de Camargo Andrade Amanda Fantini, Coque Alex de Camargo, Silva Simone L, Abuderman Abdulwahab A, Zambuzzi Willian F, Foganholi da Silva Rodrigo A
Lab. of Bioassays and Cellular Dynamics, Department of Chemical and Biological Sciences, Institute of Biosciences, Paulista State University-UNESP, Botucatu, São Paulo, Brazil.
Epigenetic Study Center and Gene Regulation-CEEpiRG, Program in Environmental and Experimental Pathology, Paulista University, São Paulo, São Paulo, Brazil.
Cell Biol Int. 2024 May;48(5):665-681. doi: 10.1002/cbin.12138. Epub 2024 Feb 29.
Epigenetic changes, particularly histone compaction modifications, have emerged as critical regulators in the epigenetic pathway driving endothelial cell phenotype under constant exposure to laminar forces induced by blood flow. However, the underlying epigenetic mechanisms governing endothelial cell behavior in this context remain poorly understood. To address this knowledge gap, we conducted in vitro experiments using human umbilical vein endothelial cells subjected to various tensional forces simulating pathophysiological blood flow shear stress conditions, ranging from normotensive to hypertensive forces. Our study uncovers a noteworthy observation wherein endothelial cells exposed to high shear stress demonstrate a decrease in the epigenetic marks H3K4ac and H3K27ac, accompanied by significant alterations in the levels of HDAC (histone deacetylase) proteins. Moreover, we demonstrate a negative regulatory effect of increased shear stress on HOXA13 gene expression and a concomitant increase in the expression of the long noncoding RNA, HOTTIP, suggesting a direct association with the suppression of HOXA13. Collectively, these findings represent the first evidence of the role of histone-related epigenetic modifications in modulating chromatin compaction during mechanosignaling of endothelial cells in response to elevated shear stress forces. Additionally, our results highlight the importance of understanding the physiological role of HOXA13 in vascular biology and hypertensive patients, emphasizing the potential for developing small molecules to modulate its activity. These findings warrant further preclinical investigations and open new avenues for therapeutic interventions targeting epigenetic mechanisms in hypertensive conditions.
表观遗传变化，尤其是组蛋白压缩修饰，已成为在持续暴露于血流诱导的层流力作用下驱动内皮细胞表型的表观遗传途径中的关键调节因子。然而，在这种情况下，控制内皮细胞行为的潜在表观遗传机制仍知之甚少。为了填补这一知识空白，我们使用人脐静脉内皮细胞进行了体外实验，这些细胞受到模拟从正常血压到高血压力的病理生理血流切应力条件的各种张力作用。我们的研究发现了一个值得注意的现象，即暴露于高切应力的内皮细胞表现出表观遗传标记H3K4ac和H3K27ac减少，同时组蛋白去乙酰化酶（HDAC）蛋白水平发生显著变化。此外，我们证明了切应力增加对HOXA13基因表达具有负调节作用，同时长链非编码RNA HOTTIP的表达增加，这表明其与HOXA13的抑制直接相关。总的来说，这些发现首次证明了组蛋白相关表观遗传修饰在响应升高的切应力力时调节内皮细胞机械信号传导过程中染色质压缩的作用。此外，我们的结果强调了了解HOXA13在血管生物学和高血压患者中的生理作用的重要性，强调了开发小分子来调节其活性的潜力。这些发现值得进一步的临床前研究，并为针对高血压病症表观遗传机制的治疗干预开辟了新途径。
