Ddah2, or dimethylarginine dimethylaminohydrolase 2, has been implicated in multiple biological processes. It was thought to be involved in metabolizing asymmetric dimethylarginine (ADMA), but recent research shows it may not directly perform this function [5]. It has key roles in innate antiviral immunity, the DDAH/ADMA/NOS/NO pathway, and is associated with conditions like leukoaraiosis, erectile dysfunction, and diabetes [1,2,3,4]. Genetic models can be valuable for studying its function in these complex biological scenarios.

In innate antiviral immunity, overexpression of Ddah2 attenuated RLR-MAVS-mediated innate antiviral signaling, while loss-of-function enhanced it both ex vivo and in mice. Ddah2 relocated to mitochondria upon viral infection, induced nitric oxide (NO) production and dynamin-related protein 1 (Drp1) activation, promoting mitochondrial fission and blocking MAVS-mediated innate immune responses [1]. In diabetic cardiomyopathy, overexpression of Ddah2 in rats alleviated myocardial fibrosis through activation of the DDAH/ADMA/NOS/NO pathway [2].

In conclusion, Ddah2 plays important roles in innate antiviral immunity and diabetic cardiomyopathy as revealed through in vivo and ex vivo functional studies. Its impact on these disease areas underscores the significance of understanding its function, and the use of genetic models such as loss-of-function experiments has been crucial in uncovering these roles [1,2].

References:

1. Huang, Shan, Li, Zexing, Wu, Zewen, Zhang, Liyun, Wang, Xi. 2021. DDAH2 suppresses RLR-MAVS-mediated innate antiviral immunity by stimulating nitric oxide-activated, Drp1-induced mitochondrial fission. In Science signaling, 14, . doi:10.1126/scisignal.abc7931. https://pubmed.ncbi.nlm.nih.gov/33850055/

2. Zhu, Zhen-Dong, Ye, Ji-Ming, Fu, Xue-Mei, Xia, Zhong-Hua, Zhang, Xuan. 2018. DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats. In International journal of molecular medicine, 43, 749-760. doi:10.3892/ijmm.2018.4034. https://pubmed.ncbi.nlm.nih.gov/30569164/

3. Fan, Ying, Gao, Qiang, Guan, Jia-Xin, Yan, Chao-Qi, Ma, Lan. . DDAH2 (-449 G/C) G allele is positively associated with leukoaraiosis in northeastern China: a double-blind, intergroup comparison, case-control study. In Neural regeneration research, 16, 1592-1597. doi:10.4103/1673-5374.303037. https://pubmed.ncbi.nlm.nih.gov/33433489/

4. Brites-Anselmi, Guilhermo, Azevedo, Ana Maria Milanez, Miyazaki, Anderson Heiji Lima, Tanus-Santos, Jose Eduardo, Lacchini, Riccardo. 2019. DDAH1 and DDAH2 polymorphisms associate with asymmetrical dimethylarginine plasma levels in erectile dysfunction patients but not in healthy controls. In Nitric oxide : biology and chemistry, 92, 11-17. doi:10.1016/j.niox.2019.08.001. https://pubmed.ncbi.nlm.nih.gov/31394201/

5. Ragavan, Vinitha N, Nair, Pramod C, Jarzebska, Natalia, Cellini, Barbara, Rodionov, Roman N. 2023. A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase. In Nature communications, 14, 3392. doi:10.1038/s41467-023-38467-9. https://pubmed.ncbi.nlm.nih.gov/37296100/