Clark Michael D, Kim Yerin, Romero Cesar A, Kang Dong Won, Baek Kyung In, Song Eun Ju, Kellum Cailin E, Bowman-Kirigin Jay A, Park Christian, Kapoor Vir, Pollock Jennifer S, Jo Hanjoong
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States.
Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States.
bioRxiv. 2025 Jun 27:2025.06.24.660441. doi: 10.1101/2025.06.24.660441.
Hypertension (HTN), the chronic elevation of blood pressure, accounts for more atherosclerotic cardiovascular disease deaths than any other modifiable risk factor. In the arteries, stable blood flow (s-flow) drives healthy, atheroprotective endothelial cell (EC) functions including nitric oxide (NO) production, barrier function, and anti-inflammatory programs via the action of flow-sensitive proteins. We showed that s-flow stimulates Heart-of-Glass 1 (HEG1) protein expression, localization to cell-cell junctions, and secretion from ECs. We found that conditional, endothelial cell-specific knockout of ( ) exacerbates atherosclerosis, however the mechanism was unknown. Here, we report a new role of HEG1 in controlling EC dysfunction, hypertension and atherosclerosis. We discover a novel mechanism: HEG1 regulates NO bioavailability via a flow-dependent HEG1-eNOS interaction (endothelial nitric oxide synthase, NOS3). develops spontaneous hypertension and severe atherosclerosis, both of which are effectively treated by Angiotensin-Converting Enzyme inhibition (ACEi). UK BioBank and Swedish cohort studies reveal that plasma HEG1 levels are associated with hypertension and cardiovascular disease risk. Our findings suggest HEG1 may serve as a biomarker to advance personalized therapies for EC dysfunction, hypertension, and atherosclerosis.
高血压（HTN），即血压的慢性升高，在动脉粥样硬化性心血管疾病死亡中所占比例高于任何其他可改变的风险因素。在动脉中，稳定血流（s-flow）通过血流敏感蛋白的作用驱动健康的、具有抗动脉粥样硬化保护作用的内皮细胞（EC）功能，包括一氧化氮（NO）生成、屏障功能和抗炎程序。我们发现s-flow刺激玻璃心1（HEG1）蛋白表达、定位于细胞间连接并从内皮细胞分泌。我们发现（ ）的条件性、内皮细胞特异性敲除会加剧动脉粥样硬化，但其机制尚不清楚。在此，我们报告HEG1在控制内皮细胞功能障碍、高血压和动脉粥样硬化方面的新作用。我们发现一种新机制：HEG1通过依赖血流的HEG1-eNOS相互作用（内皮型一氧化氮合酶，NOS3）调节NO生物利用度。（ ）会发展为自发性高血压和严重动脉粥样硬化，两者均可通过血管紧张素转换酶抑制（ACEi）有效治疗。英国生物银行和瑞典队列研究表明，血浆HEG1水平与高血压和心血管疾病风险相关。我们的研究结果表明，HEG1可能作为一种生物标志物，推动针对内皮细胞功能障碍、高血压和动脉粥样硬化的个性化治疗。
