Mahgoup Elsayed M, Khaleel Sahar A, El-Mahdy Mohamed A, Zweier Jay L
Department of Internal Medicine, Division of Cardiovascular Medicine, and the EPR Center, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.
Department of Internal Medicine, Division of Cardiovascular Medicine, and the EPR Center, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Free Radic Biol Med. 2025 Feb 16;228:339-349. doi: 10.1016/j.freeradbiomed.2024.12.057. Epub 2024 Dec 31.
Cytoglobin (Cygb) regulates vascular tone by modulating nitric oxide (NO) metabolism in vascular smooth muscle cells (VSMCs). In the presence of its cytochrome B5a (B5)/B5 reductase-isoform-3 (B5R) reducing system, Cygb controls NO metabolism via oxygen-dependent NO dioxygenation. Electronic cigarette (EC) use has been shown to induce vascular dysfunction and decrease NO bioavailability; however, the role of Cygb-mediated NO metabolism in the pathophysiology of this process has not been previously investigated. Therefore, we utilized aortic VSMCs with EC vape extract (ECE) exposure to elucidate the effects of EC vape constituents on NO degradation and alterations in the process of Cygb-mediated NO metabolism. VSMCs were exposed to ECE, either nicotine-free (ECEV) or nicotine-containing (ECEN), for various durations. NO decay rates were measured along with cellular expression of Cygb and its B5/B5R reducing system. Exposure to ECEV led to a much higher rate of NO consumption by VSMCs, with an even larger effect following ECEN exposure. With 4 h of exposure, a modest increase in NO decay rate occurred that was followed by much higher increases with exposure times of 24-48 h. This effect was paralleled by upregulation of Cygb and B5/B5R expression. siRNA-mediated knock-down of Cygb expression largely reversed this ECE-induced increase in NO metabolism rate. Thus, ECE exposure led to increased Cygb-mediated NO metabolism in VSMCs with diminished NO bioavailability, which in turn can play a key role in EC-induced vascular dysfunction.
细胞珠蛋白（Cygb）通过调节血管平滑肌细胞（VSMCs）中的一氧化氮（NO）代谢来调节血管张力。在其细胞色素B5a（B5）/B5还原酶同工型3（B5R）还原系统存在的情况下，Cygb通过氧依赖性NO双加氧作用控制NO代谢。电子烟（EC）的使用已被证明会导致血管功能障碍并降低NO生物利用度；然而，Cygb介导的NO代谢在此过程病理生理学中的作用此前尚未得到研究。因此，我们利用暴露于电子烟烟雾提取物（ECE）的主动脉VSMCs来阐明电子烟烟雾成分对NO降解以及Cygb介导的NO代谢过程变化的影响。VSMCs暴露于无尼古丁（ECEV）或含尼古丁（ECEN）的ECE中不同时长。测量NO衰减率以及Cygb及其B5/B5R还原系统的细胞表达。暴露于ECEV导致VSMCs消耗NO的速率更高，暴露于ECEN后影响更大。暴露4小时后，NO衰减率有适度增加，随后在24 - 48小时暴露时增加幅度更大。这种效应与Cygb和B5/B5R表达上调平行。siRNA介导的Cygb表达敲低在很大程度上逆转了ECE诱导的NO代谢率增加。因此，ECE暴露导致VSMCs中Cygb介导的NO代谢增加，同时NO生物利用度降低，这反过来可能在电子烟诱导的血管功能障碍中起关键作用。
