BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease.
BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease.
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DOI：
10.3390/ijms231810715
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发表时间：
2022-09-14
影响因子：
5.6
通讯作者：
Dokun, Ayotunde O.
中科院分区：
文献类型：
--
作者：
Mani, Arul M.;Dhanabalan, Karthik;Lamin, Victor;Wong, Thomas;Singh, Madhu, V;Dokun, Ayotunde O.
外周动脉疾病（PAD）的特征是下肢血流受损，导致肢体缺血性损伤。糖尿病和PAD患者通常有更严重的缺血性肢体损伤和截肢，但所涉及的机制知之甚少。先前，我们确定BAG 3作为小鼠7号染色体上称为肢体挽救QTL 1的小鼠遗传基因座内的基因，其确定C57 Bl/6小鼠中缺血性损伤后肢体坏死的程度。BAG 3缺陷是否在糖尿病PAD中观察到的严重缺血性损伤中起作用尚不清楚。在体外，我们发现模拟缺血增强了原代人骨骼肌细胞中BAG 3的表达，而BAG 3敲低增加了坏死性凋亡标志物并降低了细胞活力。在体内，与正常食物饮食（NCD）喂养的小鼠相比，来自高脂肪饮食（HFD）喂养的小鼠的后肢的缺血骨骼肌显示出较差的BAG 3表达，并且这与增加的截肢相关。来自HFD小鼠后肢的缺血骨骼肌中的BAG 3过表达挽救了肢体截肢并改善了自噬、坏死性凋亡、骨骼肌功能和再生。因此，缺血性骨骼肌中BAG 3缺乏可能通过自噬和坏死性凋亡途径导致糖尿病PAD中缺血性肢体损伤的严重程度。
Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.
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影响因子：
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发表时间：
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影响因子：
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作者：
Dokun, Ayotunde O.;Chen, Lingdan;Annex, Brian H.
通讯作者：
Annex, Brian H.