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Malaria Infection Depletes Hepatic DDAH1, a Regulator of Endothelial Nitric Oxide Synthesis

Friday, November 08, 2013 — Poster Session III

10:00 a.m. – 12:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • J.H. Chertow
  • M.S. Alkaitis
  • G. Nardone
  • H. Ackerman


Impaired endothelial nitric oxide (NO) synthesis is associated with risk of death from malaria. Homeostasis of the arginine to ADMA ratio is maintained by hepatic dimethylarginine dimethylaminohydrolase-1 (DDAH1). We hypothesized that malaria infection causes DDAH1 dysfunction, dysregulated ADMA metabolism, and impaired NO synthesis. To test this hypothesis, we infected C57Bl/6 mice with Plasmodium berghei ANKA. Six days after inoculation, protein levels of hepatic DDAH1 fell by 55% compared to uninfected controls (p < 0.0001). Concurrently, the proportion of arginine to ADMA fell from 118 ± 28 in control animals to 87 ± 22 in infected animals (p < 0.001). ADMA levels in hepatic tissue were elevated in infected animals 1.12 ± 0.5 uM compared to control animals 0.5 ± 0.3 uM, indicating DDAH1 degradation may result in local ADMA accumulation (p <0.0001). Blood nitrite levels fell from 0.53 ± 0.1 uM in control animals to 0.36 ± 0.1 uM in infected animals, consistent with impaired NO synthesis (p < 0.01). Loss of DDAH1 protein in the liver may be a potential mechanism explaining the dysregulation of ADMA metabolism and the impairment of NO synthesis that occurs during severe malaria.

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