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

Author(s)

Salerno, Alessandro G. ; Rentz, Thiago ; Dorighello, Gabriel G. ; Marques, Ana Carolina ; Lorza-Gil, Estela ; Wanschel, Amarylis C. B. A. ; de Moraes, Audrey ; Vercesi, Anibal E. ; Oliveira, Helena C. F.

• Document type: Journal article
• Source: Biochemical Journal; v. 476, p. 21-pg., 2019-12-01.

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: 11/15103-4 - 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 Opportunities: Scholarships in Brazil - Master
• 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 Opportunities: Scholarships in Brazil - Master
• 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 Opportunities: Scholarships in Brazil - Post-Doctoral
• 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 Opportunities: Research Projects - Thematic Grants
• 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 Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants