PDF(Pubmed)
Abstract：
Diabetics are more vulnerable to SARS-CoV-2 neurological manifestations. The molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes are unclear. We hypothesize that SARS-CoV-2 exacerbates diabetes-induced cerebrovascular oxidative stress and inflammation via activation of the destructive arm of the renin-angiotensin-aldosterone system (RAAS) and Toll-like receptor (TLR) signaling. SARS-CoV-2 spike protein was injected in humanized ACE2 transgenic knock-in mice. Cognitive functions, cerebral blood flow, cerebrovascular architecture, RAAS, and TLR signaling were used to determine the effect of SARS-CoV-2 spike protein in diabetes. Studies were mirrored in vitro using human brain microvascular endothelial cells treated with high glucose-conditioned media to mimic diabetic conditions. Spike protein exacerbated diabetes-induced cerebrovascular oxidative stress, inflammation, and endothelial cell death resulting in an increase in vascular rarefaction and diminished cerebral blood flow. SARS-CoV-2 spike protein worsened cognitive dysfunction in diabetes compared to control mice. Spike protein enhanced the destructive RAAS arm at the expense of the RAAS protective arm. In parallel, spike protein significantly exacerbated TLR signaling in diabetes, aggravating inflammation and cellular apoptosis vicious circle. Our study illustrated that SAR-CoV-2 spike protein intensified RAAS and TLR signaling in diabetes, increasing cerebrovascular damage and cognitive dysfunction.
摘要：
糖尿病患者更容易受到SARS-CoV-2神经系统表现的影响。SARS-CoV-2诱导糖尿病脑血管功能障碍的分子机制尚不清楚。我们假设SARS-CoV-2通过激活肾素-血管紧张素-醛固酮系统（RAAS）和Toll样受体（TLR）信号的破坏性臂，加剧了糖尿病引起的脑血管氧化应激和炎症。在人源化ACE2转基因敲入小鼠中注射SARS-CoV-2刺突蛋白。认知功能，脑血流量,脑血管结构，RAAS,和TLR信号用于确定SARS-CoV-2刺突蛋白在糖尿病中的作用。使用用高葡萄糖条件培养基处理的人脑微血管内皮细胞在体外模拟糖尿病状况。Spike蛋白加剧了糖尿病诱导的脑血管氧化应激，炎症,和内皮细胞死亡导致血管稀疏增加和脑血流量减少。与对照小鼠相比，SARS-CoV-2刺突蛋白使糖尿病的认知功能障碍恶化。尖峰蛋白以RAAS保护臂为代价增强了破坏性的RAAS臂。并行,spike蛋白显著加剧了糖尿病患者的TLR信号,加重炎症和细胞凋亡的恶性循环。我们的研究表明SAR-CoV-2刺突蛋白增强了糖尿病患者的RAAS和TLR信号,增加脑血管损伤和认知功能障碍。
