160 - Mitochondrial NADP(H)-transhydrogenase expression in macrophages is a novel player that reduces atherosclerosis (ID 477)
Abstract
Background and Aims
The atherosclerosis prone LDL receptor knockout mice (Ldlr-/-, C57BL/6J background) carry a deletion of the NADP(H)-transhydrogenase gene (Nnt) encoding the mitochondrial enzyme that catalyzes NADPH synthesis. Here we hypothesize that both increased NADPH consumption (due to increased steroidogenesis) and decreased NADPH generation (due to Nnt deficiency) in Ldlr-/- mice contribute to establish a macrophage oxidative stress and increase atherosclerosis development.
Methods
We compared peritoneal macrophages from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. We determined oxidants production, genes and proteins expression, lipid accumulation and atherosclerosis in bone marrow transplanted Ldlr-/- mice.
Results
We found increased oxidants production in both mitochondria and macrophages according to a gradient: double mutant > single mutant > wild-type. We also observed a parallel upregulation of mitochondrial biogenesis (PGC1a, TFAM and respiratory complexes levels) and inflammatory (iNOS, IL6 and IL1b) markers in single and double mutant macrophages. When exposed to modified LDL, the single and double mutant cells exhibited significant increases in lipid accumulation leading to foam cell formation, the hallmark of atherosclerosis. Nnt deficient cells showed upregulation of CD36 and downregulation of ABCA1 transporters what may explain lipid accumulation in macrophages. Finally, Nnt wild-type bone marrow transplantation into LDLr-/- mice resulted in reduced diet induced atherosclerosis.
Conclusions
In conclusion, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process.
