Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress

Abstract

Background Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethylarginine (ADMA) levels are increased, which contributes to airway nitric oxide deficiency, oxidative stress and inflammation. Overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme degrading ADMA, exerts protective effects in animal models. However, the impact of DDAH1/ADMA on PM2.5-induced lung injury has not been investigated. Methods Ddah1−/− and DDAH1-transgenic mice, as well as their respective wild-type (WT) littermates, were exposed to either filtered air or airborne PM2.5 (mean daily concentration ~ 50 µg/m3) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM2.5 and/or exogenous ADMA (2 mg/kg) via intratracheal instillation every other day for 2 weeks. Inflammatory response, oxidative stress and related gene expressions in the lungs were examined. In addition, RAW264.7 cells were exposed to PM2.5 and/or ADMA and the changes in intracellular oxidative stress and inflammatory response were determined. Results Ddah1−/− mice developed more severe lung injury than WT mice after long-term PM2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM2.5-exposed mice, Ddah1 deficiency increased protein expression of p-p65, iNOS and Bax, and decreased protein expression of Bcl-2, SOD1 and peroxiredoxin 4. Conversely, DDAH1 overexpression significantly alleviated lung injury, attenuated pulmonary oxidative stress and inflammation, and exerted opposite effects on those proteins in PM2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM2.5-induced lung injury, oxidative stress and inflammation. In PM2.5-exposed macrophages, ADMA aggravated the inflammatory response and oxidative stress in an iNOS-dependent manner. Conclusion Our data revealed that DDAH1 has a marked protective effect on long-term PM2.5 exposure-induced lung injury.

DDAH1 recruits peroxiredoxin 1 and sulfiredoxin 1 to preserve its activity and regulate intracellular redox homeostasis

“…DDAH1 also exerted significant protective effects against CCl 4 -induced hepatotoxicity. These results were consistent with our previous findings that DDAH1 has antioxidant effects on aged and diabetic kidneys [ 10 ], fatty livers [ 7 ], and PM 2.5 -exposed lungs [ 11 ]. As ADMA accumulation can not only inhibit NO production but can also promote ROS production by uncoupling NOS [ 12 ], it is undisputed that the antioxidant effect of DDAH1 under stress conditions is related to ADMA degradation.…”

“…Ddah1 deletion also attenuated the induction of SRXN1 and PRDX4 expression in the livers of CCl 4 -treated mice. The regulatory effects of DDAH1 on antioxidant enzymes have also been observed in PM 2.5 -exposed lungs [ 11 ] and in patients with cardiotoxin-induced muscle injury [ 9 ], acute myocardial infarction-induced heart failure [ 43 ] and diabetic nephropathy [ 10 ]. Notably, the underlying mechanism by which DDAH1 regulates antioxidant enzymes is complex and enzyme/cell/tissue dependent.…”

“…The generation and genetic backgrounds of Ddah1 -/- mice and DDAH1 transgenic (DDAH1-TG) mice were described in our previous studies [ 11 , 22 ]. In brief, Ddah1 gene was first deleted in the sperm through crossing the DDAH1 flox/flox mice with the protamine (Prm)-Cre mice.…”

“…Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is recognized as a critical enzyme for the degradation of asymmetric dimethylarginine (ADMA) [ 6 ], which inhibits nitric oxide synthase (NOS) by competing with L-Arg. Our studies have consistently shown that DDAH1 can repress oxidative stress in different disease models, including fatty liver [ 7 , 8 ], muscle injury and regeneration [ 9 ], diabetic nephropathy [ 10 ] and PM 2.5 -exposed lung [ 11 ]. As ADMA accumulation under pathological conditions can promote ROS production by uncoupling NOS [ 12 ] or upregulating the renin–angiotensin system [ 13 ], the antioxidant effect of DDAH1 may be partly attributed to ADMA degradation.…”

Integrative proteomics and metabolomics analysis of non‐observable acute effect level PM2.5 induced accumulative effects in AC16 cells

“…A previous review reported that oxidative stress and inflammation was one of the hallmarks of environmental insults, and the overwhelming oxidative stress results in cell death and organ damage (Peters et al, 2021). The increased oxidative stress was a key mechanism that PM 2.5 induced damages (Gao et al, 2022; Jiang, Liang, et al, 2021; Jo et al, 2021; Li et al, 2021). The biological oxidation has initiated in the A5‐24 h group, and the stress has significantly shown in A5‐G12.…”