Correlation between Mitochondrial Reactive Oxygen and Severity of Atherosclerosis.

Gabriel G Dorighello,Samara F Kiihl,Helena C F Oliveira,Rodrigo R Catharino,Bruno A Paim,Anibal E Vercesi,Mônica S Ferreira

doi:10.1155/2016/7843685

Gabriel G Dorighello, Samara F Kiihl + Show 5 more

Open Access

https://doi.org/10.1155/2016/7843685

Copy DOI

Abstract

Atherosclerosis has been associated with mitochondria dysfunction and damage. Our group demonstrated previously that hypercholesterolemic mice present increased mitochondrial reactive oxygen (mtROS) generation in several tissues and low NADPH/NADP+ ratio. Here, we investigated whether spontaneous atherosclerosis in these mice could be modulated by treatments that replenish or spare mitochondrial NADPH, named citrate supplementation, cholesterol synthesis inhibition, or both treatments simultaneously. Robust statistical analyses in pooled group data were performed in order to explain the variation of atherosclerosis lesion areas as related to the classic atherosclerosis risk factors such as plasma lipids, obesity, and oxidative stress, including liver mtROS. Using three distinct statistical tools (univariate correlation, adjusted correlation, and multiple regression) with increasing levels of stringency, we identified a novel significant association and a model that reliably predicts the extent of atherosclerosis due to variations in mtROS. Thus, results show that atherosclerosis lesion area is positively and independently correlated with liver mtROS production rates. Based on these findings, we propose that modulation of mitochondrial redox state influences the atherosclerosis extent.

Highlights

Oxidative stress seems to be a common denominator unifying a variety of classic risk factors mode of action that leads to atherosclerosis [1]
It has been well recognized that mitochondrial dysfunctions such as opening of the permeability transition pore directly promote inflammation and oxidative stress, phenomena involved in several cardiometabolic diseases [8, 9, 12]
Diet-induced atherosclerosis was evaluated in LDLr−/− treated or not with 120 mM citrate drinking solution [14] during two weeks

Summary

Introduction

Oxidative stress seems to be a common denominator unifying a variety of classic risk factors mode of action that leads to atherosclerosis [1]. Our group have previously shown that mitochondria from various tissues of the hypercholesterolemic atherosclerosis-prone LDL receptor knockout mice (LDLr−/−) release more ROS than wild type controls [10]. This model presents reduced content of mitochondrial NADPH [10], the main reducing power for the antioxidant system glutathione and thioredoxine reductase/peroxidase [11]. This LDLr−/− mitochondrial prooxidant state rendered the organelle more susceptible to membrane permeability transition (MPT).

Methods

Results

Conclusion