Asymmetric dimethylarginine triggers macrophage apoptosis via the endoplasmic reticulum stress pathway

Abstract

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is emerging as a key contributing factor in atherogenesis, a process in turn known to involve macrophage apoptosis. The aim of this study was to determine the effect of ADMA on macrophage apoptosis, with specific reference to the endoplasmic reticulum (ER) stress pathway. Macrophage apoptosis was evaluated by Annexin V- Propidium iodide (PI) and Hoechst 33258 staining assays. Levels of the ER stress marker glucose regulated protein 78 (GRP78) were characterized by western blot. Levels of the proapoptotic C/EBP-homologous protein (CHOP) were evaluated by western blot and reverse transcription polymerase chain reaction (RT-PCR), and caspase-4 activity was measured using a colorimetric protease assay kit. We observed ADMA dose- and time-dependent increases in macrophage levels of GRP78. Similar ADMA dose- and time-dependent increases were detected in intracellular caspase-4 activity and macrophage apoptosis, all of which were sensitive to treatment with siRNAs for protein kinase RNA-like ER kinase and inositol-requiring protein-1 (IRE1), the ADMA antagonist L-arginine, as well as inhibitors of eukaryotic translation initiation factor-2 (salubrinal), IRE1 (irestatin 9389), and c-Jun N-terminal kinase (SP600125). Our results indicate that ADMA triggers macrophage apoptosis via the ER stress pathway.

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

“…Additional immunosuppressive metabolites and peptides identified and/or characterized in the CNS lymphoma microenvironment in this study and that represent potential targets include IL-10, 58-60 5-methylthioadenosine, 61,62 and dimethylarginine. 63,64 Although the biomarker and response data need to be considered in the context of small sample size of an early-phase trial, the combined results from phase 1 investigation plus a parallel analysis of low-dose lenalidomide maintenance in independent patients support the relevance of these data to the design of future studies. Notably, based on the lenalidomide maintenance data presented in this study, 2 randomized phase 2 studies are in development to evaluate low-dose lenalidomide maintenance in older PCNSL ophthalmologic examinations were performed for 6 patients at highest risk for ocular relapse (patients 1, 3-5, and 9-10) with a mean frequency of every 4 months (supplemental Table 5).…”

Arginine methylation dysfunction increased risk of acute coronary syndrome in coronary artery disease population

“…Oxidative stress, native or oxidized LDL, angiotensin II, eNOS inhibition/uncoupling and inflammation played a pivotal role in Arg residues methylation by managing PRMT/DDAH expression [ 24 – 27 ] , and meanwhile increased arginase activity reduced Arg bioavailability, both of which might contribute to lower AMI in ACS. Studies had demonstrated Arg metabolites were associated with atherosclerosis progression, [ 15 , 28 , 29 ] and even associated with atherosclerotic plaque burden and fragility. [ 30 ] Notsu et al [ 31 ] suggested that the Arg/ADMA ratio may be a sensitive marker for atherosclerosis; Tang et al [ 1 ] demonstrated that Arg/(Cit + Orn) (global arginine bioavailability ratio, GABR) might serve as a more comprehensive concept of reduced NO synthetic capacity and diminished GABR were associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for major adverse cardiovascular events.…”

Asymmetric dimethylarginine (ADMA) treatment induces apoptosis in cultured rat mesangial cells via endoplasmic reticulum stress activation

“…ADMA-induced activation of ER stress signaling, which induces mesangial cell apoptosis ADMA promotes cellular dysfunction via ER stress signaling (Guo, Ding, 2014, Hong, Gao, 2015, Zhou, Zhou, 2009). To confirm whether ADMA activates ER stress signaling in mesangial cells, mesangial cells were treated with ADMA and then observed for marker proteins.…”

“…Increased serum ADMA level is associated with various kidney diseases, including CKD. In addition, ADMA induces cellular dysfunction via ER stress signaling in a variety of cell types (Zhou et al, ; Guo et al, ; Hong et al, ). Previously, we reported that activated ER stress is associated with mesangial cell apoptosis (Lim et al, ).…”