OBJECTIVE Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.

中文翻译：

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镰状细胞性贫血介导可通过抑制JNK（c-Jun N末端激酶）来预防颈动脉扩张重塑。

目的镰状细胞性贫血（SCA）引起慢性炎症和多器官损伤。对动脉并发症的了解较少，最明显的是儿童中风增加。在小鼠模型中研究了蛋白水解机制，生物力学后果和药物抑制策略，为镰状细胞病引起的大动脉损伤的机制和干预研究提供了平台。方法和结果：使用Townes的SCA人源化转基因小鼠模型检验以下假设：颈动脉的弹性层板和结构损伤随年龄增加而在SCA纯合子（镰状细胞性贫血纯合基因型[SS]）小鼠中由于炎症而加速激活蛋白水解酶的信号通路。与杂合子同窝对照（镰刀状细胞性状杂合基因型[AS]）相比，SS小鼠在1个月时观察到了弹性薄片分裂。组织蛋白酶K（一种强大的胶原酶和弹性蛋白酶）的阳性免疫染色证实了SS颈动脉蛋白水解活性的增强。通过磁共振血管造影定量较大的横截面积，并且还测量了SS颈动脉的动脉顺应性增加。用SP600125抑制JNK（c-jun N末端激酶）信号传导可显着降低SS小鼠的组织蛋白酶K表达，弹性蛋白片段化和颈动脉周长。到5个月大时，用JNK抑制剂治疗SS小鼠可减轻持续的内侧变薄和胶原蛋白降解。结论SCA引起的动脉重塑是由JNK信号传导，组织蛋白酶蛋白上调，和弹性蛋白和胶原蛋白的降解。Townes小鼠的示范确立了其在动脉血管病变，相关并发症以及SCA引起的大动脉损伤的治疗性干预机制研究中的效用。