DDAH1 deficiency exacerbates cerebral vascular endothelial dysfunction by aggravating BBB disruption and oxidative stress in thoracic blast-induced brain injury

• Published in: Experimental neurology 2025-01, Vol.383, p.114994, Article 114994
• Main Authors: Cong, Peifang, Tong, Changci, Mao, Shun, Shi, Lin, Hou, Mingxiao, Liu, Yunen
• Format: Article
• Language: English
• Subjects: Amidohydrolases - deficiency; Amidohydrolases - genetics; Amidohydrolases - metabolism; Animals; Blast Injuries - complications; Blast Injuries - pathology; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain Injuries - etiology; Brain Injuries - metabolism; Brain Injuries - pathology; Cerebral vascular endothelial dysfunction; DDAH1; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress - physiology; Thoracic blast-induced brain injury
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2024.114994

As terrorist incidents and underground explosion events have become more frequent around the world, brain injury caused by thoracic blast exposure has been more highlighted due to its injured organ, subsequent social and economic burden. It has been reported dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays important roles in regulating vascular endothelial injury repair and angiogenesis, but its role in thoracic blast-induced brain injury remains to be explained. This study seeks to investigate the mechanism of DDAH1 on thoracic blast-induced brain injury. 40 C57BL/6 wild type mice and 40 DDAH1 knockout mice were randomly and equally divided into control group and blast group, respectively. The integrity of blood-brain barrier (BBB) was detected by Evans blue test. The serum inflammatory factors, nitric oxide (NO) contents, and asymmetric dimethylarginine (ADMA) levels were determined through ELISA. HE staining and reactive oxygen species (ROS) detection were performed for histopathological changes. Western blot was used to detect the proteins related to oxidative stress, tight junction, focal adhesion, vascular endothelial injury, and the DDAH1/ADMA/eNOS signaling pathway. DDAH1 deficiency aggravated thoracic blast-induced BBB leakage, inflammatory response, and the increased levels of inflammatory-related factors. Additionally, DDAH1 deficiency also increased ROS generation, MDA and IRE-α expression. Regarding cerebral vascular endothelial dysfunction, DDAH1 deficiency increased the expression of MCAM, FN1, LIMK1, VEGF, MMP9, Vimentin and N-cadherin, while lowering the expression of FMR1, Occludin, claudin-3, claudin-5, Lyn, LIMA1, Glrb, Sez6, Dystrophin, and phosphorylation of VASP. Also, DDAH1 deficiency exacerbated explosion-induced increase of ADMA and decrease of eNOS activity and NO contents. Thus, we conclude that DDAH1 could prevent cerebral vascular endothelial dysfunction and related injury by inhibiting ADMA signaling and increasing eNOS activity in thoracic blast induced brain injury. •DDAH1 was significantly downregulated in the thoracic blast-induced brain injury of mice.•Thoracic blast exposure impaired tight junction, focal adhesion, and vascular endothelial function in the brain.•DDAH1 deficiency exacerbates cerebral vascular endothelial dysfunction in thoracic blast-induced brain injury.•DDAH1 deficiency aggravates brain injury by decreasing NO content through inhibiting DDAH1/ADMA/eNOS signaling pathway.