Abstract
Oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction is an initial step toward atherosclerosis development. Mitochondria damage correlates with ox-LDL-induced endothelial injury through an undefined mechanism. We explored the role of optic atrophy 1 (Opa1)-related mitochondrial fusion and mitophagy in ox-LDL-treated endothelial cells, focusing on mitochondrial damage and cell apoptosis. Oxidized low-density lipoprotein treatment reduced endothelial cell viability by increasing apoptosis. Endothelial cell proliferation and migration were also impaired by ox-LDL. At the molecular level, mitochondrial dysfunction was induced by ox-LDL, as demonstrated by decreased mitochondrial membrane potential, increased mitochondrial reactive oxygen species production, augmented mitochondrial permeability transition pore openings, and elevated caspase-3/9 activity. Mitophagy and mitochondrial fusion were also impaired by ox-LDL. Opa1 overexpression reversed this effect by increasing endothelial cell viability and decreasing apoptosis. Interestingly, inhibition of mitophagy or mitochondrial fusion through transfection of siRNAs against Atg5 or Mfn2, respectively, abolished the protective effects of Opa1. Our results illustrate the role of Opa1-related mitochondrial fusion and mitophagy in sustaining endothelial cell viability and mitochondrial homeostasis under ox-LDL stress.
Highlights
Atherosclerosis is caused by an excessive accumulation of oxidized low-density lipoproteins in the vascular intima, which is followed by plaque formation (Aquila et al, 2019; Provenzano et al, 2019; Ramel et al, 2019)
Our data demonstrated that endothelial cell viability Oxidized low-density lipoprotein (ox-LDL) Induces Mitochondrial Damage was significantly decreased upon ox-LDL treatment, a result that was caused by increased apoptosis
Our results reported that endothelial apoptosis is mainly induced by mitochondrial damage, which was characterized by decreased mitochondrial potential, increased mitochondrial reactive oxygen species (ROS) production, augmented mitochondrial permeability transition pore (mPTP) opening, and elevated caspase-9/Bax activity
Summary
Atherosclerosis is caused by an excessive accumulation of oxidized low-density lipoproteins (ox-LDLs) in the vascular intima, which is followed by plaque formation (Aquila et al, 2019; Provenzano et al, 2019; Ramel et al, 2019). Several mechanisms have been proposed to explain atherosclerosis formation—such as oxidative stress, lipid metabolism disorder, and inflammation—endothelial dysfunction is accepted as the prevailing factor (Huang et al, 2014; Peng et al, 2015; Kario et al, 2020; Marangoni et al, 2020). A better understanding of the molecular mechanism underlying ox-LDL-induced endothelial cell apoptosis will drive atherosclerosis research forward and aid in the development of new therapeutic approaches. Reactive oxygen species-mediated oxidative stress promotes endothelial senescence (Hou et al, 2020), leading to impaired angiogenesis. Many researches have observed the role of mitochondrial damage in triggering endothelial dysfunction upon ox-LDL treatment (Li et al, 2018, Li et al, 2020; Yuan et al, 2019; Xie et al, 2020), suggesting an urgent need for therapies that protect endothelial mitochondria in order to reduce atherosclerosis development
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