Genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme for intracellular triglyceride (TG) hydrolysis, causes TG-deposit cardiomyovasculopathy (TGCV), a recently identified rare cardiovascular disorder (ORPHA code: 565612) in humans. One of the major characteristics of TGCV is a novel type of diffuse and concentric coronary atherosclerosis with ATGL-deficient smooth muscle cells (SMCs). Patients with TGCV have intractable coronary artery disease. Therefore, it is crucial to investigate the mechanisms underlying vascular lesions in ATGL deficiency using animal models. Cuff injury is an experimental procedure to induce vascular remodeling with neointimal formation with SMCs after placing a cuff around the adventitial side of the artery without direct influence on endothelium. We report the effect of cuff injury on femoral arteries of ATGL-knockout (ATGL⁻/⁻) mice. Cuff-induced concentric neointimal formation with migrating SMCs was exacerbated in ATGL⁻/⁻ mice, mimicking atherosclerotic lesions in patients with TGCV. In the media, cell death of SMCs and loss of elastic fibers increased. Perivascular infiltrating cells expressing tumor necrosis factor-α (TNF-α) were more prominent in ATGL⁻/⁻ mice than in wild-type (WT) mice. In Boyden chamber experiments, a greater number of ATGL⁻/⁻ SMCs migrated in response to TNF-α compared to WT SMCs. These data, for the first time, demonstrated that outside-in signaling by cuff-induced neointimal formation where paracrine stimuli from adventitial infiltrating cells may lead to neointimal formation and mediolysis in ATGL-deficient conditions. Cuff injury might be a valuable model for understanding the mechanisms underlying the development of atherosclerotic lesions in patients with TGCV.

中文翻译：

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股骨袖损伤引起的外向内信号在脂肪甘油三酯脂肪酶敲除小鼠中诱导明显的血管病变。

脂肪甘油三酯脂肪酶 (ATGL) 是细胞内甘油三酯 (TG) 水解的限速酶，其遗传缺陷会导致 TG 沉积型心肌血管病 (TGCV)，这是一种最近在人类中发现的罕见心血管疾病（ORPHA 代码：565612）。TGCV 的主要特征之一是一种新型的弥漫性和向心性冠状动脉粥样硬化，伴有 ATGL 缺陷型平滑肌细胞 (SMC)。TGCV 患者患有顽固性冠状动脉疾病。因此，使用动物模型研究 ATGL 缺乏症血管病变的机制至关重要。袖带损伤是一种实验过程，在不直接影响内皮的情况下，在动脉外膜侧放置袖带后，用 SMC 诱导血管重塑，形成新内膜。我们报告了袖带损伤对 ATGL 基因敲除 (ATGL⁻/⁻) 小鼠股动脉的影响。在 ATGL⁻/⁻ 小鼠中，袖带诱导的具有迁移性 SMC 的同心新内膜形成加剧，类似于 TGCV 患者的动脉粥样硬化病变。在培养基中，SMC 的细胞死亡和弹性纤维的损失增加。表达肿瘤坏死因子-α (TNF-α) 的血管周围浸润细胞在 ATGL⁻/⁻ 小鼠中比在野生型 (WT) 小鼠中更为突出。在 Boyden 室实验中，与 WT SMC 相比，更多数量的 ATGL⁻/⁻ SMC 迁移以响应 TNF-α。这些数据首次证明了通过袖带诱导的新内膜形成的由外向内信号传导，其中来自外膜浸润细胞的旁分泌刺激可能导致新内膜形成和 ATGL 缺陷条件下的介质溶解。