Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Biomedical, Biological, and Chemical Engineering Department, University of Missouri, Columbia, Missouri.
Am J Physiol Heart Circ Physiol. 2022 Feb 1;322(2):H167-H180. doi: 10.1152/ajpheart.00431.2021. Epub 2021 Dec 10.
Consumption of diets high in fat, sugar, and salt (Western diet, WD) is associated with accelerated arterial stiffening, a major independent risk factor for cardiovascular disease (CVD). Women with obesity are more prone to develop arterial stiffening leading to more frequent and severe CVD compared with men. As tissue transglutaminase (TG2) has been implicated in vascular stiffening, our goal herein was to determine the efficacy of cystamine, a nonspecific TG2 inhibitor, at reducing vascular stiffness in female mice chronically fed a WD. Three experimental groups of female mice were created. One was fed regular chow diet (CD) for 43 wk starting at 4 wk of age. The second was fed a WD for the same 43 wk, whereas a third cohort was fed WD, but also received cystamine (216 mg/kg/day) in the drinking water during the last 8 wk on the diet (WD + C). All vascular stiffness parameters assessed, including aortic pulse wave velocity and the incremental modulus of elasticity of isolated femoral and mesenteric arteries, were significantly increased in WD- versus CD-fed mice, and reduced in WD + C versus WD-fed mice. These changes coincided with respectively augmented and diminished vascular wall collagen and F-actin content, with no associated effect in blood pressure. In cultured human vascular smooth muscle cells, cystamine reduced TG2 activity, F-actin:G-actin ratio, collagen compaction capacity, and cellular stiffness. We conclude that cystamine treatment represents an effective approach to reduce vascular stiffness in female mice in the setting of WD consumption, likely because of its TG2 inhibitory capacity. This study evaluates the novel role of transglutaminase 2 (TG2) inhibition to directly treat vascular stiffness. Our data demonstrate that cystamine, a nonspecific TG2 inhibitor, improves vascular stiffness induced by a diet rich in fat, fructose, and salt. This research suggests that TG2 inhibition might bear therapeutic potential to reduce the disproportionate burden of cardiovascular disease in females in conditions of chronic overnutrition.
高脂肪、高糖和高盐饮食（西式饮食，WD）的摄入与动脉僵硬度加速有关，而动脉僵硬度是心血管疾病（CVD）的一个主要独立危险因素。与男性相比，肥胖女性更容易发生动脉僵硬度，从而导致更频繁和更严重的 CVD。由于组织转谷氨酰胺酶（TG2）与血管僵硬度有关，我们的目标是确定半胱胺（一种非特异性 TG2 抑制剂）在降低慢性 WD 喂养的雌性小鼠血管僵硬度方面的功效。为此，我们创建了三个实验组的雌性小鼠。一组从 4 周龄开始，连续 43 周喂食常规饮食（CD）。第二组喂食相同的 WD 43 周，而第三组喂食 WD，但在最后 8 周的饮食中，也在饮用水中接受半胱胺（216mg/kg/天）（WD+C）。在 WD-喂食的小鼠中，所有评估的血管僵硬度参数，包括主动脉脉搏波速度和分离的股动脉和肠系膜动脉的弹性增量模量，均显著高于 CD 喂食的小鼠，而 WD+C 喂食的小鼠则低于 WD 喂食的小鼠。这些变化与血管壁胶原和 F-肌动蛋白含量分别增加和减少相对应，而血压没有相关影响。在培养的人血管平滑肌细胞中，半胱胺降低了 TG2 活性、F-肌动蛋白：G-肌动蛋白比值、胶原压实能力和细胞硬度。我们得出结论，半胱胺治疗代表了一种有效的方法，可以降低 WD 消耗情况下雌性小鼠的血管僵硬度，可能是因为其 TG2 抑制能力。这项研究评估了转谷氨酰胺酶 2（TG2）抑制作为直接治疗血管僵硬度的新作用。我们的数据表明，半胱胺，一种非特异性的 TG2 抑制剂，可以改善由富含脂肪、果糖和盐的饮食引起的血管僵硬度。这项研究表明，TG2 抑制可能具有治疗潜力，以降低慢性营养过剩条件下女性心血管疾病的不成比例负担。
