Asymmetric dimethylarginine exacerbates cognitive dysfunction associated with cerebrovascular pathology

Abstract

Abbreviations: [Ca 2+ ] i , intracellular calcium ion; • O − 2 , superoxide anion; AD, Alzheimer's disease; ADMA, asymmetric dimethylarginine; Aβ, amyloid-β peptide; BBB, blood-brain barrier; hBMVEC, human brain microvessel endothelial cell; DAPI, 4′,6-diamidino-2-phenylindole, dihydrochloride; EB, Evans blue; eNOS, endothelial nitric oxide synthase; GFAP, glial fibrillary acidic protein; GSH, glutathione; GSNO, S-nitrosoglutathione; Iba-1, ionized calcium-binding adaptor molecule 1; L-NIO, N 5 -(1-Iminoethyl)-L-ornithine dihydrochloride; MLC, myosin light chain; MLC, myosin light chain; NO, nitric oxide; N-Tyr, 3-nitrotyrosine; ONOOˉ, peroxynitrite; SD, standard deviation; SIN-1, 3-morpholinosydnonimine chloride; TEER, transendothelial electrical resistance; Tg-SwDI, transgenic mice expressing human β-amyloid precursor protein Swedish, Dutch, Iowa mutant; VCID, vascular cognitive impairment and dementia; WT, wild type. AbstractAsymmetric dimethylarginine (ADMA), an endogenous inhibitor and uncoupler of nitric oxide synthase, has gained attention as a risk factor for cardiac disease, metabolic syndrome, and cerebrovascular disease. In this study, we investigated the role of systemic ADMA overburden in cerebromicrovascular pathology associated with cognitive dysfunction using APPSwDI transgenic mice expressing human β-amyloid precursor protein Swedish (Tg-SwDI), a model of cerebrovascular β-amyloidosis.To induce systemic overburden of ADMA, Tg-SwDI mice were treated with a daily dose of exogenous ADMA. ADMA treatment resulted in elevated ADMA levels in the blood and brain of Tg-SwDI mice. ADMA treatment induced the brain nitrosative stress and inflammation as well as enhanced the brain Aβ deposition and cognitive impairment in Tg-SwDI mice. However, ADMA treatment had no such effects on wild type mice. ADMA treatment also exacerbated brain microvascular pathology in Tg-SwDI mice as observed by increased blood-brain barrier dysfunction, loss of tight junction proteins, increased endothelial stress fibers, and decreased microvessel density in the brain. In addition, similar observations were made in cultured human brain microvessel endothelial cells, where ADMA in the presence of VEGF-induced endothelial cell signaling for F-actin stress fiber inducing endothelial barrier dysfunction. Overall, these data document the potential role of ADMA in the cognitive pathology under conditions of cerebrovascular β-amyloidosis. K E Y W O R D Sactin stress fiber, Alzheimer's disease, asymmetric dimethylarginine (ADMA), brain endothelial barrier, endothelial nitric oxide synthase (eNOS), nitric oxide, vascular cognitive impairment and dementia (VCID) | 6809 CHOI et al.

Vascular and immunopathological role of Asymmetric Dimethylarginine (ADMA) in Experimental Autoimmune Encephalomyelitis

“…Our laboratory has recently reported that ADMA induces endothelial/vascular dysfunction by interacting with VEGF [33]. Based on these studies, we analysed blood levels of ADMA and VEGF in EAE mice.…”

“…Next, we investigated the effect of ADMA overburden on clinical EAE disease. Recently, we have reported that systemic treatment of C57BL/6 mice with a daily dose of ADMA (50mg/kg/day/ip) increases the levels of ADMA in the blood [33]. Based on these data, we treated EAE mice with the same daily dose of ADMA starting on the day of disease onset (day 11 post‐immunization).…”

“…Recently, our laboratory has reported that ADMA enhances endothelial/vascular dysfunction under neuropathological conditions [33]. To investigate the effect of ADMA overburden on BBB functions and integrity in EAE animals, we performed Evans blue extravasation assay.…”

“…EAE animals had an increased blood level of HCy and reduced DDAH activities in the kidney and liver and thus elevation of blood levels of ADMA (Figure 1). Overburden of blood AMDA by daily treatment of ADMA [33] caused exacerbation of clinical EAE disease (Figure 2) with increased loss of myelin and axons in the spinal cord (Figure 3) as well as increased BBB disruption and mononuclear cell infiltration into the CNS (Figure 4). ADMA treatment also promoted T H 1‐ and T H 17‐mediated immune responses in the spleen but without affecting Treg‐mediated immune response under EAE conditions (Figure 5).…”

Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation

“…A loss-of-function Ddah1 promoter polymorphism is associated with increased susceptibility to cardiovascular diseases and thrombosis stroke 12 . Thus, these SNPs of Ddah1 are likely associated with metabolic syndrome including metabolic bone diseases 13 , 14 . Therefore, our initial aim was to investigate if the loss-of-function Ddah1 promoter polymorphism is associated with osteoporosis.…”