Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Department of Nursing and Health Sciences, Faculty of Nursing and Health Sciences, Notre Dame University-Louaize, Beirut, Lebanon.
Oxid Med Cell Longev. 2020 May 21;2020:6425782. doi: 10.1155/2020/6425782. eCollection 2020.
Hypertension induces vascular hypertrophy, which changes blood vessels structurally and functionally, leading to reduced tissue perfusion and further hypertension. It is also associated with dysregulated levels of the circulating adipokines leptin and adiponectin (APN). Leptin is an obesity-associated hormone that promotes vascular smooth muscle cell (VSMC) hypertrophy. APN is a cardioprotective hormone that has been shown to attenuate hypertrophic cardiomyopathy. In this study, we investigated the molecular mechanisms of hypertension-induced VSMC remodeling and the involvement of leptin and APN in this process. To mimic hypertension, the rat portal vein (RPV) was mechanically stretched, and the protective effects of APN on mechanical stretch-induced vascular remodeling and the molecular mechanisms involved were examined by using 10 g/ml APN. Mechanically stretching the RPV significantly decreased APN protein expression after 24 hours and APN mRNA expression in a time-dependent manner in VSMCs. The mRNA expression of the APN receptors AdipoR1, AdipoR2, and T-cadherin significantly increased after 15 hours of stretch. The ratio of APN/leptin expression in VSMCs significantly decreased after 24 hours of mechanical stretch. Stretching the RPV for 3 days increased the weight and [H]-leucine incorporation significantly, whereas APN significantly reduced hypertrophy in mechanically stretched vessels. Stretching the RPV for 10 minutes significantly decreased phosphorylation of LKB1, AMPK, and eNOS, while APN significantly increased p-LKB1, p-AMPK, and p-eNOS in stretched vessels. Mechanical stretch significantly increased p-ERK1/2 after 10 minutes, whereas APN significantly reduced stretch-induced ERK1/2 phosphorylation. Stretching the RPV also significantly increased ROS generation after 1 hour, whereas APN significantly decreased mechanical stretch-induced ROS production. Exogenous leptin (3.1 nM) markedly increased GATA-4 nuclear translocation in VSMCs, whereas APN significantly attenuated leptin-induced GATA-4 nuclear translocation. Our results decipher molecular mechanisms of APN-induced attenuation of mechanical stretch-mediated vascular hypertrophy, with the promising potential of ultimately translating this protective hormone into the clinic.
高血压会引起血管肥大，从而改变血管的结构和功能，导致组织灌注减少和进一步的高血压。它还与循环脂肪因子瘦素和脂联素（APN）的失调水平有关。瘦素是一种与肥胖相关的激素，可促进血管平滑肌细胞（VSMC）肥大。APN 是一种心脏保护激素，已被证明可减轻肥厚性心肌病。在这项研究中，我们研究了高血压引起的 VSMC 重塑的分子机制，以及瘦素和 APN 在这个过程中的作用。为了模拟高血压，我们对大鼠门静脉（RPV）进行机械拉伸，并使用 10μg/ml 的 APN 检查 APN 对机械拉伸诱导的血管重塑的保护作用及其涉及的分子机制。机械拉伸 RPV 可显著降低 24 小时后 VSMC 中的 APN 蛋白表达和 APN mRNA 表达，呈时间依赖性。拉伸 15 小时后，APN 受体 AdipoR1、AdipoR2 和 T-钙粘蛋白的 mRNA 表达显著增加。24 小时机械拉伸后，VSMC 中的 APN/瘦素表达比值显著降低。机械拉伸 RPV 3 天可显著增加重量和[H]-亮氨酸掺入量，而 APN 可显著减少机械拉伸血管的肥大。机械拉伸 RPV 10 分钟可显著降低 LKB1、AMPK 和 eNOS 的磷酸化水平，而 APN 可显著增加拉伸血管中 p-LKB1、p-AMPK 和 p-eNOS 的水平。机械拉伸 10 分钟后，p-ERK1/2 显著增加，而 APN 可显著减少 ERK1/2 磷酸化。机械拉伸 RPV 还可在 1 小时后显著增加 ROS 的产生，而 APN 可显著减少机械拉伸引起的 ROS 产生。外源性瘦素（3.1nM）可显著增加 VSMC 中 GATA-4 的核转位，而 APN 可显著减弱瘦素诱导的 GATA-4 核转位。我们的研究结果揭示了 APN 减轻机械拉伸介导的血管肥大的分子机制，为最终将这种保护性激素转化为临床应用提供了有希望的潜力。
