Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders.
Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders.
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DOI：
10.5551/jat.rv17008
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Miyazaki A
中科院分区：
文献类型：
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作者：
Miyazaki T;Miyazaki A
慢性血管疾病如动脉粥样硬化、动脉瘤、糖尿病性血管病/视网膜病以及纤维化和增殖性血管疾病通常因退行性损伤的进展而复杂化，其特征在于内皮功能障碍、血管/免疫细胞中的凋亡/坏死细胞死亡、细胞外基质的重塑或弹性板层的破坏。越来越多的证据表明，功能失调的钙蛋白酶蛋白水解系统和血管中钙蛋白酶蛋白代谢缺陷导致退行性疾病。在血管内皮细胞中，由钙蛋白酶-1和-2同工酶组成的常规钙蛋白酶的过度活化可导致细胞-细胞连接的解体、一氧化氮合酶的功能障碍、Janus激酶/信号转导子和转录级联激活子的敏化以及前列腺素I2的耗竭，这有助于退行性疾病。除了内皮细胞功能障碍外，钙蛋白酶过度活化导致巨噬细胞中的炎性损伤和血管平滑肌细胞中过度的纤维化/增殖信号传导。此外，钙蛋白酶-6（一种非蛋白水解的非常规钙蛋白酶）参与巨噬细胞向促动脉粥样硬化表型的转化，导致细胞中低密度脂蛋白胆固醇的胞饮沉积。在这里，我们讨论了最近取得的进展，在我们的理解如何钙蛋白酶有助于退行性血管疾病。
Chronic vascular diseases such as atherosclerosis, aneurysms, diabetic angiopathy/retinopathy as well as fibrotic and proliferative vascular diseases are generally complicated by the progression of degenerative insults, which are characterized by endothelial dysfunction, apoptotic/necrotic cell death in vascular/immune cells, remodeling of extracellular matrix or breakdown of elastic lamella. Increasing evidence suggests that dysfunctional calpain proteolytic systems and defective calpain protein metabolism in blood vessels contribute to degenerative disorders. In vascular endothelial cells, the overactivation of conventional calpains consisting of calpain-1 and -2 isozymes can lead to the disorganization of cell-cell junctions, dysfunction of nitric oxide synthase, sensitization of Janus kinase/signal transducer and activator of transcription cascades and depletion of prostaglandin I2, which contributes to degenerative disorders. In addition to endothelial cell dysfunctions, calpain overactivation results in inflammatory insults in macrophages and excessive fibrogenic/proliferative signaling in vascular smooth muscle cells. Moreover, calpain-6, a non-proteolytic unconventional calpain, is involved in the conversion of macrophages to a pro-atherogenic phenotype, leading to the pinocytotic deposition of low-density lipoprotein cholesterol in the cells. Here, we discuss the recent progress that has been made in our understanding of how calpain contributes to degenerative vascular disorders.