Mitochondrial Integrity and Function in Atherogenesis

Abstract

Background-Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS. Methods and Results-We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E Ϫ/Ϫ mice but also preceded atherogenesis in young apolipoprotein E Ϫ/Ϫ mice. Apolipoprotein E Ϫ/Ϫ mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a phenotype of accelerated atherogenesis at arterial branch points. Key Words: atherosclerosis Ⅲ muscle, smooth Ⅲ antioxidants R eactive species (RS) define a collective grouping of reactive oxygen and nitrogen species that can alter the biological functions of essential molecules such as lipids, proteins, and DNA. Numerous studies have linked excess RS generation with vascular lesion formation and functional defects. [1][2][3] This association has been reported for various RS models and species. 4 -6 A role for RS in atherogenesis is supported by epidemiological evidence of links between common risk factors for coronary artery disease and increased levels of RS. [7][8][9] Among the extensively studied intracellular systems capable of generating RS in vascular cells are the NADH/NADPH oxidase, xanthine oxidase, lipoxygenase, and cyclooxygenase systems. 6,10 -12 Mitochondria are biologically important sources and targets for RS. 13,14 However, their role as mediators of oxidative disease processes such as atherogenesis has not been examined. We recently reported that exposure of vascular cells to RS in vitro results in preferential mitochondrial DNA (mtDNA) damage and dysfunction and that mtDNA damage is a very sensitive marker for RS-mediated cellular effects. 15 In addition to the potential role of mtDNA damage as a marker of ambient oxidative stress, oxidative damage to the mitochondrion can lead to decreased oxidative energetic capacity (via impaired oxidative phosphorylation) and increased generation of intracellular RS. 15-17 Thus, we hypothesized that mitochondrial dysfunction accentuates atherosclerosis by modulating the phenotype of vascular cells and that measurements of mtDNA damage reflect RS-mediated atherosclerosis risk. Conclusions-MitochondrialUsing human aortic specimens and a murine model of early atherogenesis (the apolipoprotein E null, apoE Ϫ/Ϫ ), we examined the correlation between mtDNA damage and atherogenesis and sought to determine whether mtDNA damage is a cause or an effect in this pr...

Oxidative Stress Mediates Tumor Necrosis Factor-α–Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes

“…2,16 Recent studies have indicated that mtDNA damage affects mitochondrial function and thus plays an important role in the pathophysiology of various cardiovascular diseases, such as heart failure 17 and atherosclerosis. 18 This vicious circle may result in myocardial functional and structural damage in heart failure. The equivalent results observed between in vivo and in vitro indicate that TNF-␣ plays an important role in oxidative stress in the pathogenesis of myocardial remodeling and failure.…”

Reactive Oxygen Species in Inflammation and Tissue Injury

“…Mitochondrial-derived oxidative stress has also been implicated in chronic inflammation, cancer progression (206), diabetes mellitus (148,152,(317)(318)(319)378), and atherosclerosis (21,258). Mitochondrial-derived ROS (MtROS) also contributes to LPS-mediated production of pro-inflammatory cytokines IL-1b, IL-6, and TNF-a (48).…”

Critical Pathways in Heart Function: Bis(2-chloroethoxy)methane-Induced Heart Gene Transcript Change in F344 Rats

“…Thus, the response to CEM exposure involved changes that take place at the cell membrane (e.g., response to extracellular signals, ion transport, cell adhesion). DISCUSSION Cardiac disease leads to impairment of energy supply through mitochondria damage (Ballinger, 2005;Ballinger et al, 2002;Bulteau et al, 2005;Kang and Hamasaki, 2005;Rosenberg, 2004). Thus, in the CEM rat model of heart toxicity, where mitochondria damage occurs, we explored changes in heart transcripts associated with energy supply and demand, and how changes in heart transcripts may help to maintain heart function.…”