Mitochondrial dysfunction in atherosclerosis

Increased production of reactive oxygen species in mitochondria, accumulation of mitochondrial DNA damage, and progressive respiratory chain dysfunction are associated with atherosclerosis or cardiomyopathy in human investigations and animal models of oxidative stress. Moreover, major precursors of atherosclerosis-hypercholesterolemia, hyperglycemia, hypertriglyceridemia, and even the process of aging-all induce mitochondrial dysfunction. Chronic overproduction of mitochondrial reactive oxygen species leads to destruction of pancreatic beta-cells, increased oxidation of low-density lipoprotein and dysfunction of endothelial cells-factors that promote atherosclerosis. An additional mechanism by which impaired mitochondrial integrity predisposes to clinical manifestations of vascular diseases relates to vascular cell growth. Mitochondrial function is required for normal vascular cell growth and function. Mitochondrial dysfunction can result in apoptosis, favoring plaque rupture. Subclinical episodes of plaque rupture accelerate the progression of hemodynamically significant atherosclerotic lesions. Flow-limiting plaque rupture can result in myocardial infarction, stroke, and ischemic/reperfusion damage. Much of what is known on reactive oxygen species generation and modulation comes from studies in cultured cells and animal models. In this review, we have focused on linking this large body of literature to the clinical syndromes that predispose humans to atherosclerosis and its complications.     

The putative role of mitochondrial dysfunction in hypertension

Hypertension is a condition associated with oxidative stress, endothelial dysfunction, and increased vascular resistance, representing probably both a cause and a consequence of elevated levels of reactive oxygen (ROS) and nitrogen (RNS) species. Mitochondria are important sites of ROS production, and a mitochondrial dysfunction, preceding endothelial dysfunction, might favor the development of hypertension. ROS production may also be induced by RNS, which inhibit the respiratory chain and may be generated through the action of a mitochondrial NO synthase. Mitochondrial uncoupling proteins are involved in both experimental and human hypertension. Finally, an excessive production of ROS may damage mitochondrial DNA, with resultant impairment in the synthesis of some components of the respiratory chain and further ROS production, a vicious cycle that may be implicated in hypertensive states.     

The Putative Role of Mitochondrial Dysfunction in Hypertension

Hypertension is a condition associated with oxidative stress, endothelial dysfunction, and increased vascular resistance, representing probably both a cause and a consequence of elevated levels of reactive oxygen (ROS) and nitrogen (RNS) species. Mitochondria are important sites of ROS production, and a mitochondrial dysfunction, preceding endothelial dysfunction, might favor the development of hypertension. ROS production may also be induced by RNS, which inhibit the respiratory chain and may be generated through the action of a mitochondrial NO synthase. Mitochondrial uncoupling proteins are involved in both experimental and human hypertension. Finally, an excessive production of ROS may damage mitochondrial DNA, with resultant impairment in the synthesis of some components of the respiratory chain and further ROS production, a vicious cycle that may be implicated in hypertensive states.     

线粒体功能障碍与血管内皮损伤的研究进展

线粒体功能障碍会导致ATP的生成减少,活性氧的产生增加,被认为是血管内皮损伤的触发因素之一。许多因素与线粒体功能障碍有关,如线粒体DNA突变、线粒体融合与分裂失衡、线粒体自噬受损等。本文综述了线粒体的质量控制过程和线粒体功能障碍在血管内皮损伤中的作用机制,以期为动脉粥样硬化的有效防治提供新的思路。     

衰老与血管内皮功能障碍

血管内皮功能障碍是血管老化的早期病理改变之一,对动脉粥样硬化的发生发展起到非常重要的作用。老年性血管内皮功能障碍主要表现在内皮一氧化氮、前列环素和内皮衍生超极化因子等一系列内皮舒血管物质的生成减少或其生物利用度下降,而内皮素、血栓素和活性氧等一些内皮缩血管物质的生成或血管对这些物质的敏感性增加。另外,衰老导致的血管内皮修复能力减退也起到一定的作用。现就衰老对这些因素的影响及其分子机制作一概述。     

氧化应激与心血管疾病

大量证据表明活性氧的慢性或急性过度产生在心血管疾病的发生发展中起重要作用。活性氧通过信号通路介导心肌细胞肥大和凋亡;通过灭活一氧化氮等机制导致内皮功能紊乱。在动脉粥样硬化、心肌缺血再灌注损伤、高血压、心力衰竭等一些主要心血管疾病的病理生理学中,氧化应激扮演关键角色。     

Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis

Increased oxidative stress in vascular cells plays a key role in the development of endothelial dysfunction and atherosclerosis. Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. This study was undertaken to test the hypothesis that, UCP2 functions as an inhibitor of the atherosclerotic process in endothelial cells. Adenovirus-mediated UCP2 (Ad-UCP2) overexpression led to a significant increase in endothelial nitric oxide synthase (eNOS) and decrease in endothelin-1 mRNA expression in human aortic endothelial cells (HAECs). Moreover, UCP2 inhibited the increase in ROS production and NF-kappaB activation, and apoptosis of HAECs induced by lysophophatidylcholine (LPC) and linoleic acid. LPC and linoleic acid caused mitochondrial calcium accumulation and transient mitochondrial membrane hyperpolarization, which was followed by depolarization. UCP2 overexpression prevented these processes. In isolated rat aorta, Ad-UCP2 infection markedly improved impaired vascular relaxation induced by LPC. The data collectively suggest that UCP2, functions as a physiologic regulator of ROS generation in endothelial cells. Thus, measures to increase UCP2 expression in vascular endothelial cells may aid in preventing the development and progression of atherosclerosis in patients with metabolic syndrome.     

硝基化修饰蛋白质在心血管内皮功能障碍中的作用

内皮功能障碍作为多种心血管疾病共同的特征之一,与过量表达的活性氧(ROS)/活性氮(RNS)密切相关。超氧阴离子与一氧化氮(NO)反应可以生成氧化能力更强的过氧亚硝酸盐,可以通过氧化多种蛋白质耗竭NO,导致内皮收缩与舒张功能障碍,在多种心血管疾病中发挥了重要的作用。该文通过综述硝基化修饰蛋白质产生的途径及其在心血管疾病中促进内皮功能紊乱的可能机制,讨论了ROS/RNS介导的硝基化修饰与内皮功能障碍之间相互促进,共同推动心血管疾病进程的关系。该文还讨论了清除过氧亚硝酸盐、抑制ROS产生途径以及直接增强内皮细胞功能的治疗策略在内皮功能障碍相关的心血管疾病中的应用,可以为进一步研究蛋白质硝基化修饰这一蛋白质翻译后修饰作为干预靶点在心血管疾病中的作用提供参考。     

Mitochondrial Reactive Oxygen Species and Risk of Atherosclerosis

High levels of reactive oxygen species (ROS) are observed in chronic human diseases such as obesity, type 2 diabetes, atherosclerosis, and cardiovascular diseases. In addition to the presence of oxidative stress, these diseases are also characterized by deregulated inflammatory responses. Our first aim is to discuss distinct molecular pathways that determine the rate of mitochondrial ROS (mtROS) production and identify agents and enzymes that disrupt the balance between ROS generation and ROS elimination. Recent studies exploring the mechanisms linking ROS and inflammation found that ROS derived from mitochondria act as signal-transducing molecules that provoke endothelial dysfunction associated with uncoupling of nitric oxide synthase, induce the infiltration and activation of inflammatory cells, and increase apoptosis of endothelial and vascular smooth muscle cells. Therefore, our second aim is to give a comprehensive overview of the role of mtROS in all these processes contributing to atherosclerotic lesion progression and causing plaque erosion and rupture. Our third aim is to emphasize the role of the inflammatory toll-like receptor 2/NF-κB signaling pathway in the induction of pro-inflammatory cytokines and mtROS production in relation to insulin resistance, type 2 diabetes, and atherosclerosis. Because mtROS play an active role in several pathogenic mechanisms there is need for mitochondria-targeted antioxidants. Preliminary experiments in cell and animal models of cardiovascular diseases showed that some mitochondria-targeted antioxidants indeed reduce ROS production. However, wide-spread use in humans requires the development of specific and sensitive assays to evaluate mitochondrial oxidative stress and the development of orally active compounds.     

Cigarette smoking as a risk factor for atherosclerosis and renal disease: Novel pathogenic insights

Cigarette smoking is the major cause of preventable morbidity and mortality in the United States. It is a major risk factor for atherosclerotic vascular disease and recently was identified as an important risk factor in the progression of chronic kidney disease. Several compounds in cigarette smoke, including nicotine and reactive aldehydes (eg, acrolein), have been implicated as mediators of endothelial dysfunction and atherosclerosis in smokers. In addition, studies have demonstrated that nicotine induces endothelial dysfunction in humans and accelerates atherosclerosis in animals. Large clinical trials have suggested that cigarette smoking is a risk factor for progression of chronic kidney disease in diabetics and nondiabetics, and in polycystic kidney disease, lupus nephritis, and IgA nephropathy. Recent studies suggest that nicotine has powerful mitogenic effects and induces extracellular matrix production in human mesangial cells via reactive oxygen species generation. These effects of nicotine may play a major role in the pathogenic mechanisms that mediate the deleterious effects of smoking in renal disease.     

Effects of blood pressure and glucose on endothelial function

Hypertension and diabetes mellitus are associated with accelerated atherosclerosis and an increased prevalence of cardiovascular disease. Loss of the modulatory role of the endothelium can be considered the link between these conditions and cardiovascular disease. Substantial evidence suggests that vasodilation mediated by endothelium-derived nitric oxide (NO) is impaired in animal models and in patients with hypertension and diabetes mellitus. NO is a principal factor involved in the anti-atherosclerotic properties of the endothelium. Therefore, the pathogenesis of hypertensive and diabetic vascular disease may involve a reduced bioavailability of endothelium-derived NO. Inactivation of NO by reactive oxygen species is an important common mechanism by which endothelial dysfunction may occur. This review summarizes experimental and clinical evidence for impaired NO-mediated vasodilation in the presence of high blood pressure and hyperglycemia. A better understanding of the mechanisms leading to endothelial dysfunction may unmask new preventive strategies to reduce cardiovascular morbility and mortality in these conditions.     

NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease

Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O2*-) and hydrogen peroxide (H2O2) appear most important in redox signaling. Whereas O2*- predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO*), H2O2 influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H2O2 in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase-derived H2O2 amplifies its own production. Recent studies have shown that H2O2 stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H2O2-dependent pathological signaling in vascular cells, thus contributing to vascular disease development. The latest progress on Nox functions in vascular cells is also discussed [Nox for NAD(P)H oxidases, representing a family of novel NAD(P)H oxidases].     

Mitochondria in vascular disease

Mitochondria are often regarded as the powerhouse of the cell by generating the ultimate energy transfer molecule, ATP, which is required for a multitude of cellular processes. However, the role of mitochondria goes beyond their capacity to create molecular fuel, to include the generation of reactive oxygen species, the regulation of calcium, and activation of cell death. Mitochondrial dysfunction is part of both normal and premature ageing, but can contribute to inflammation, cell senescence, and apoptosis. Cardiovascular disease, and in particular atherosclerosis, is characterized by DNA damage, inflammation, cell senescence, and apoptosis. Increasing evidence indicates that mitochondrial damage and dysfunction also occur in atherosclerosis and may contribute to the multiple pathological processes underlying the disease. This review summarizes the normal role of mitochondria, the causes and consequences of mitochondrial dysfunction, and the evidence for mitochondrial damage and dysfunction in vascular disease. Finally, we highlight areas of mitochondrial biology that may have therapeutic targets in vascular disease.     

The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging

Aging is associated with a progressive loss of skeletal muscle mass and strength and the mechanisms mediating these effects likely involve mitochondrial DNA (mtDNA) mutations, mitochondrial dysfunction and the activation of mitochondrial-mediated apoptosis. Because the mitochondrial genome is densely packed and close to the main generator of reactive oxygen species (ROS) in the cell, the electron transport chain (ETC), an important role for mtDNA mutations in aging has been proposed. Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in mammals, including humans, and often coincide with significant tissue dysfunction. Here, we examine the evidence supporting a causative role for mtDNA mutations in aging and sarcopenia. We review experimental outcomes showing that mtDNA mutations, leading to mitochondrial dysfunction and possibly apoptosis, are causal to the process of sarcopenia. Moreover, we critically discuss and dispute an important part of the mitochondrial 'vicious cycle' theory of aging which proposes that accumulation of mtDNA mutations may lead to an enhanced mitochondrial ROS production and ever increasing oxidative stress which ultimately leads to tissue deterioration and aging. Potential mechanism(s) by which mtDNA mutations may mediate their pathological consequences in skeletal muscle are also discussed.     

The relationships among hyperuricemia, endothelial dysfunction, and cardiovascular diseases: molecular mechanisms and clinical implications

Uric acid is the end product of purine metabolism. Its immediate precursor, xanthine, is converted to uric acid by an enzymatic reaction involving xanthine oxidoreductase. Uric acid has been formerly considered a major antioxidant in human plasma with possible beneficial anti-atherosclerotic effects. In contrast, studies in the past two decades have reported associations between elevated serum uric acid levels and cardiovascular events, suggesting a potential role for uric acid as a risk factor for atherosclerosis and related diseases. In this paper, the molecular pattern of uric acid formation, its possible deleterious effects, as well as the involvement of xanthine oxidoreductase in reactive oxygen species generation are critically discussed. Reactive oxygen species contribute to vascular oxidative stress and endothelial dysfunction, which are associated with the risk of atherosclerosis. Recent studies have renewed attention to the xanthine oxidoreductase system, since xanthine oxidoreductase inhibitors, such as allopurinol and oxypurinol, would be capable of preventing atherosclerosis progression by reducing endothelial dysfunction. Also, beneficial effects could be obtained in patients with congestive heart failure. The simultaneous reduction in uric acid levels might contribute to these effects, or be a mere epiphenomenon of the drug action. The molecular mechanisms involved are discussed.     

Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences

Increased production of reactive oxygen species (ROS) has been implicated in the pathogenesis of cardiovascular diseases. Enzymatic systems such as the mitochondrial respiratory chain, vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS) produce superoxide anion (O2*-) in vascular cells. While some O2(*-) rapidly degrades by reacting with nitric oxide (NO*), the O2*- signal preserved by dismutation into hydrogen peroxide (H2O2) exerts prolonged signaling effects. This review focuses on patterns and mechanisms whereby H2O2 modulates different aspects of endothelial cell function including endothelial cell growth and proliferation, endothelial apoptosis, endothelium-dependent vasorelaxation, endothelial cytoskeletal reorganization and barrier dysfunction, endothelial inflammatory responses, and endothelium-regulated vascular remodeling. These modulations of endothelial cell function may at least partially underlie H2O2 contribution to the development of vascular disease.     

Linking mitochondrial dysfunction to neurodegeneration in lysosomal storage diseases

Lysosomal storage diseases (LSD) are inborn errors of metabolism resulting in multisystem disease. Central nervous system involvement, often with progressive neurodegeneration, accounts for a large portion of the morbidity and mortality seen in many LSD. Available treatments fail to prevent or correct neurologic symptoms and decline. Emerging evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of LSD-associated neurodegeneration. Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration. Here, we review the current evidence for mitochondrial dysfunction in neuronal models of seven LSD, including GM1-gangliosidosis, mucopolysaccharidosis IIIC, multiple sulfatase deficiency, Krabbe disease, Gaucher disease, Niemann Pick disease type C and the neural ceroid lipofuscinoses and outline current experimental therapies aimed at restoring mitochondrial function and neuroprotection in LSD.