Liang Li-Mei, Cai Peng-Cheng, Yu Fan, He Xin-Liang, Song Lin-Jie, Lu Yu-Zhi, Niu Qian, Zhou Ya-Ya, Jiang Li-Juan, Jiang Ye-Han, Jia Zi-Heng, Zhao Li-Qin, Wang Meng, Cheng Pei-Pei, Chen Shuai-Jun, Feng Xiao, Li Qian, Cui Xiao-Lin, Xiong Liang, Xiang Fei, Wang Xiaorong, Ye Hong, Ma Wan-Li
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; NHC Key Laboratory of Pulmonary Immune-related Diseases, Guiyang, China.
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Biochim Biophys Acta Mol Basis Dis. 2025 Nov;1871(8):168015. doi: 10.1016/j.bbadis.2025.168015. Epub 2025 Aug 13.
Airway remodeling is a key point in asthma. Airway smooth muscle cells (ASMCs) play a pivotal role in airway remodeling. Cyclic AMP (cAMP) provides energy which is necessary for airway relaxation. Lack of energy in ASMCs results in dysregulation of airway relaxation as well as airway remodeling. The type 9 adenylyl cyclase (ADCY9) is a widely distributed adenylyl cyclase and contributes to basal cAMP production. However, the role of ADCY9 in asthma was still poorly understood. In this study, firstly ADCY9 rs2230739 gene polymorphism in asthma patients was investigated. There was a single nonsynonymous sequence variant at nucleotide 2316 where it was noted an A (wild-type) or G which was corresponding an Ile changed to Met at position 772 (Ile772Met). Next, we found this Ile to Met polymorphism in ADCY9 decreased reversibility of FEV1/FVC%. Moreover, changes of the Ile to Met in ADCY9 predicted further decline of FEV1/FVC% and FEV1% by Cox proportional hazard regression model. Then mechanisms of ADCY9 in asthma were explored. Asthma-related cytokines decreased ADCY9 expression and cellular cAMP levels which reduced airway relaxation ability and promoted airway remodeling. On the contrary, over-expression of ADCY9 protein attenuated airway remodeling. However, ADCY9 over-expression with missense mutant protein (ADCY9-772Met) failed to prevent airway smooth muscle remodeling. Taken together, An Ile to Met polymorphism in ADCY9 promoted airway obstruction and remodeling in asthma.
气道重塑是哮喘的关键环节。气道平滑肌细胞（ASMCs）在气道重塑中起关键作用。环磷酸腺苷（cAMP）为气道舒张提供必要能量。ASMCs中能量缺乏会导致气道舒张功能失调以及气道重塑。9型腺苷酸环化酶（ADCY9）是一种广泛分布的腺苷酸环化酶，有助于基础cAMP的产生。然而，ADCY9在哮喘中的作用仍知之甚少。在本研究中，首先对哮喘患者的ADCY9 rs2230739基因多态性进行了研究。在核苷酸2316处存在一个非同义序列变异，发现有A（野生型）或G，相应地在第772位（Ile772Met）处异亮氨酸变为甲硫氨酸。接下来，我们发现ADCY9中这种异亮氨酸到甲硫氨酸的多态性降低了FEV1/FVC%的可逆性。此外，通过Cox比例风险回归模型，ADCY9中异亮氨酸到甲硫氨酸的变化预测了FEV1/FVC%和FEV1%的进一步下降。然后探讨了ADCY9在哮喘中的作用机制。哮喘相关细胞因子降低了ADCY9的表达和细胞内cAMP水平，从而降低了气道舒张能力并促进了气道重塑。相反，ADCY9蛋白的过表达减弱了气道重塑。然而，ADCY9错义突变蛋白（ADCY9-772Met）的过表达未能阻止气道平滑肌重塑。综上所述，ADCY9中异亮氨酸到甲硫氨酸的多态性促进了哮喘中的气道阻塞和重塑。
