Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Lack of mitochondrial NADP(H)-transhydrogenase expression in macrophages exacerbates atherosclerosis in hypercholesterolemic mice

Full text
Author(s):
Salerno, Alessandro G. [1] ; Rentz, Thiago [1] ; Dorighello, Gabriel G. [1] ; Marques, Ana Carolina [2] ; Lorza-Gil, Estela [1] ; Wanschel, Amarylis C. B. A. [1] ; de Moraes, Audrey [2] ; Vercesi, Anibal E. [2] ; Oliveira, Helena C. F. [1]
Total Authors: 9
Affiliation:
[1] Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, Campinas, SP - Brazil
[2] Univ Estadual Campinas, Fac Med Sci, Dept Clin Pathol, Campinas, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Biochemical Journal; v. 476, n. 24, p. 3769-3789, DEC 2019.
Web of Science Citations: 0
Abstract

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. Thus, we compared peritoneal macrophages and liver mitochondria from three C57BL/6J mice lines: Ldlr and Nnt double mutant, single Nnt mutant and wild-type. 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 up-regulation 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 deficiency cells showed up-regulation of CD36 and down-regulation 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. Therefore, Nnt plays a critical role in the maintenance of macrophage redox, inflammatory and cholesterol homeostasis, which is relevant for delaying the atherogenesis process. (AU)

FAPESP's process: 11/15101-1 - Nitric oxide and mitochondrial permeability transition in hypercholesterolemic mice: putative role of NADP-transhydrogenase
Grantee:Audrey de Moraes
Support type: Scholarships in Brazil - Master
FAPESP's process: 11/15103-4 - IS THE OXIDIZED STATE OF MITOCHONDRIAL NADP IN HYPERCHOLESTEROLEMIC MICE DUE TO INCREASED CHOLESTEROL SYNTHESIS OR TO NADP-TRANSIDROGENASE DEFICIENCY?
Grantee:Ana Carolina Marques
Support type: Scholarships in Brazil - Master
FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
Grantee:Aníbal Eugênio Vercesi
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/05497-0 - Contribution of increased steroidogenesis and/or NADP-transhydrogenase deficiency to the mitochondrial oxidative stress in cells from hypercholesterolemic mice
Grantee:Alessandro Gonzalez Salerno
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
Grantee:Aníbal Eugênio Vercesi
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
Grantee:Licio Augusto Velloso
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 17/02903-9 - Role of CETP expression in the macrophage redox state: possible consequences to inflammation and atherosclerosis
Grantee:Gabriel de Gabriel Taffarello Dorighello
Support type: Scholarships in Brazil - Post-Doctorate