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)	NIAID	MICROBIO-3

Authors

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

Abstract

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.