Neurodegenerative diseases: insights into pathogenic mechanisms from atherosclerosis

Increasing evidence indicates that several pathogenic mechanisms promoting atherosclerosis are also involved in neurodegenerative diseases, and that insight into the factors determining the susceptibility to, and long-term progression of, atherosclerosis may be of interest for the evolution of diseases such as Alzheimer's. Furthermore, atherosclerosis of intracranial arteries or thromboembolic consequences of atherosclerotic extracranial arteries are responsible for most ischemic events in the brain. Age-related changes of cerebrovascular atherosclerosis, and atherosclerosis in general, may therefore be important for stroke and neurodegenerative diseases affecting the elderly. In the following, pathogenic mechanism involving increased lipid peroxidation, oxidative stress, inflammation and immune responses, and fetal programming will be discussed in the context of cerebrovascular disease and aging.     

Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis

Oxidative modification of low-density lipoprotein is thought to promote arterial lipid accumulation and atherogenesis. Previous studies reported on the presence of certain lipid or protein oxidation products in lesions, although a systematic investigation measuring several oxidation parameters and the accumulation of nonoxidized lipids and antioxidants at various stages of atherosclerosis has not been performed in the same tissue. Using the intimal lipoprotein-containing fraction of human aortic lesions, we demonstrate here that cholesterol accumulated with lesion development and that this increase was already significant at the fatty streak stage. By comparison, cholesterylesters increased significantly only in fibro-fatty and more complex lesions that also contained significantly increased amounts of cholesterylester hydro(pero)xides and 27-hydroxycholesterol. Cholesterylester hydroxides were the major lipid oxidation product detected. Despite accumulation of oxidized lipid, alpha-tocopherol was also present and maintained at a comparable level over the disease process. Of the oxidized protein moieties measured only o,o-dityrosine increased with disease, although chlorotyrosines were present at relatively high levels in all lesions compared to healthy vessels. Our data show that accumulation of nonoxidized lipid precedes that of oxidized lipid in human aortic lesions.     

Everolimus,a promising medical therapy for coronary heart disease?

Coronary heart disease is mainly caused by atherosclerosis, which is a multifactotial and systemic disease. Lipid metabolism disorder and chronic inflammation are two well accepted mechanisms leading to atherosclerosis. The key initiating process in athrogenesis is lipid retention in subendothelium. Inflammatory activity plays an important role in the whole pathogenesis of atherosclerosis. Recent investigations have demonstrated that rapamycin reduces lipid retention by increasing adipose-tissue lipase activity and decreasing lipoprotein lipase activity. Rapamycin also reduce intracellular lipid accumulation in smooth muscle cells and macrophages. Since rapamycin is a definite immunosuppressive agent, and inflammatory process has been involved in atherosclerosis, the compound would have effect on the progression of atherosclerosis through reducing inflammatory activity. Moreover, rapamycin would protect plaque from rupture by selectively clearing macrophages without affecting vascular smooth muscle cells.     

内源性睾酮在雄性高脂血症大鼠早期动脉粥样硬化形成中的作用

目的：研究内源性睾酮对雄性高脂血症大鼠早期动脉粥样硬化形成的影响及其作用机制。方法：雄性Ｗｉｓｔａｒ大鼠随机均分为正常对照组,高脂对照组,高脂去势组（切除双侧睾丸及副睾）。实验时间１２周。结果：高脂去势组与高脂对照组相比,血浆总胆固醇（ＴＣ）,甘油三酯（ＴＧ）浓度相差不明显,低密度脂蛋白（ＨＤＬ）水平较高,低密度脂蛋白（ＬＤＬ）＋极低密度脂蛋白（ＶＬＤＬ）水平较低,血浆脂质过氧化物（ＬＰＯ）水平较     

成年人群下肢动脉疾病早期变化与脂质代谢特点的相关性分析

目的 研究成年人群下肢动脉硬化早期变化与脂质代谢的临床特点,为有效地开展下肢动脉粥样硬化的一级和二级预防提供依据。方法 调查对象为年龄大于或等于40周岁的某单位人群共525人。下肢动脉硬化诊断方法使用动脉硬化早期测定仪筛检。检测成年人群耾动脉-踝动脉搏波传导速度（brachial-anklepulse wave velocity,baPWV）和踝臂指数（brachial-ankle index,ABI）,了解成年人群的血管弹性状况。血脂异常的诊断依据1997年全国血脂防治建议。结果 体检的525人中,40～49岁baPWV检测值升高者占32.8%;50～59岁baPWV检测值升高者占56%;60～69岁baPWV检测值升高者占69.8%;70～79岁baPWV检测值升高者占75%;年龄越大,baPWV检出率越高。525人中,baPWV检测值轻度升高者占13%;baPWV中度升高者占22%;重度升高者占8%。525人中血脂异常者309人,其中总胆固醇值升高、低密度脂蛋白升高伴同型半胱氨酸升高者179人,伴baPWV检测值升高者136人,达76%。结果 显示,总胆固醇值和低密度脂蛋白升高伴同型半胱氨酸升高者下肢动脉硬化发生率高（76%）。结论 深圳地区成年人群早期下肢动脉硬化与脂质代谢异常密切相关。积极治疗脂质代谢异常,开展下肢动脉粥样硬化的一级和二级预防是降低心脑血管事件的关键。     

Atherosclerosis following balloon catheter injury to the carotid artery and the aorta of hypertensive rats with normolipidemia or hyperlipidemia.

The carotid artery and abdominal aorta of hypertensive normocholesterolemic rats responded in similar manner to balloon denuding of the endothelium. One denuding resulted in an intimal fibrous plaque, while multiple such injuries increased the lipid content of the plaque and so yielded fatty-fibrous plaques, which perhaps represent an intermediate stage of atherosclerosis. In no instance did a single or multiple denuding lead to advanced atherosclerosis. Although the abdominal aorta of animals with one or with repeated denudings accumulated more lipid when placed on atherogenic died, the lesions remained essentially in the fatty-fibrous plaque category. Typical atherosclerosis was observed only occasionally and was limited to rats with multiple denudings. In rats with denuded carotid artery on an atherogenic diet classic atherosclerosis developed, especially when there were multiple episodes of injury. This was the first time the authors observed advanced atherosclerosis in the rat, and the lesions were quite comparable to human atherosclerosis. For the rat in this instance the principal factors in pathogenesis were hyperlipidemia and the repeated endothelial denudings, which promoted lipid deposit in the intimal plaques of the vessel.     

A study of atherosclerosis regression in Macaca mulatta. V. Changes in abdominal aorta and carotid and coronary arteries from animals with atherosclerosis induced for 38 months and then regressed for 24 or 48 months at plasma cholesterol concentrations of 300 or 200 mg/dl

Young adult male rhesus monkeys (Macaca mulatta) were fed an atherogenic diet for 38 months. After 38 months of atherosclerosis induction, a baseline group was selected and necropsied to determine the extent and severity of atherosclerosis before regression regimens were begun. The remaining animals were fed diets that varied in cholesterol concentration in order to maintain plasma cholesterol concentrations of approximately 200 or 300 mg/dl for either 24 or 48 months. The progression or regression of atherosclerosis in coronary arteries, abdominal aorta, and carotid arteries was determined by comparing them to the baseline group. Coronary artery atherosclerosis regressed in the majority of animals after 4 years but not after 2 years when plasma cholesterol concentrations were about 200 mg/dl. Among the animals maintained at plasma cholesterol concentrations of about 300 mg/dl, about half the animals progressed in the extent of coronary artery atherosclerosis while about half regressed. The majority of the animals that progressed in lesion extent were genetic hyperresponders to dietary cholesterol whereas those that regressed were predominantly hyporesponders, even though their plasma lipid concentrations were equivalent during the regression phase. The changes seen in atherosclerosis extent in the abdominal aorta were quite similar to the changes seen in coronary arteries. Changes at this site were not pronounced after 2 years, but after 4 years animals with plasma cholesterol concentrations of about 300 mg/dl progressed while the animals at 200 mg/dl were mostly unchanged. No evidence for atherosclerosis regression was found in the common carotid arteries or in the carotid bifurcations.     

四逆汤与维生素E抗血管内皮功能氧化损伤及防治家兔实验性动脉粥样硬化的比较研究

目的:观察比较具有清除氧自由基作用的复方中药四逆汤与抗氧化剂维生素E抗血管内皮功能氧化损伤、防治家兔实验性动脉粥样硬化(AS)的作用。方法:运用喂饲高脂饲料造家兔实验性AS模型,随机分组处理,实验结束时,取主动脉及血样品,分析各组主动脉粥样斑块面积、脂代谢及血管内皮氧化损伤指标(SOD活性、MDA含量、NO水平、ET浓度)。结果:四逆汤中、高剂量组和维生素E组的主动脉内膜脂质斑块面积与内皮氧化损伤变化(除维生素E组的SOD活性外)均明显轻于模型组(P＜0.05),四逆汤组的脂代谢紊乱指标也较模型组明显改善(P均＜0.05)。结论:四逆汤抗血管内皮功能氧化损伤、防治AS的综合疗效较维生素E为优。     

Lipid peroxidation in the etiology and pathogenesis of atherosclerosis

Reviewing the data available in the literature and their own findings, the authors consider the role of lipid peroxidation in the etiology and pathogenesis of atherosclerosis. The paper provides a good evidence for intensified peroxidation of hepatic lipids and liver-secreted atherogenic lipoproteins in atherogenesis, which is followed by blood lipid peroxides accumulation in hypercholesterolemia and atherosclerosis. The excess of aortic lipid peroxides occurs concurrently with a sharp decrease in the activity of the enzymatic systems in utilizing lipid peroxides. Accumulation of lipid peroxides in the aorta may be a factor that contributes to higher migration and proliferation of smooth muscle cells forming a cellular basis for an atherosclerotic plaque. The products of cholesterol oxidation were also reported to exert an atherogenic action.     

TRIB3参与血管动脉粥样硬化机制的探讨

正常内皮细胞功能的障碍首先表现为细胞信号蛋白表达的改变或缺陷,引起相应细胞的生物学功能降低,从而加速相关疾病的发生与进展.TRIB3是肥胖、糖尿病和动脉粥样硬化等代谢性疾病的关键枢纽蛋白,通过胰岛素抵抗、内质网应激、脂质代谢等一系列途径,加速血管动脉粥样硬化的形成与进展.因此,本文旨在探讨TRIB3如何调控机体中血脂水平、血糖代谢、血管活性,加速血管动脉粥样硬化形成的机制所在.     

Adaptation of lipid-induced satiation is not dependent on caloric density in rats

Food intake is modulated by ingestive (gastrointestinal) and post-ingestive signals; ingested fat is potent to produce short-term satiety (satiation) but this can be modified by long-term ingestion of a high fat diet. AIM: Determine whether altered lipid-induced satiation is dependent on the fat content of the diet, rather than increased caloric density or changes in adiposity. METHODS: Initial experiments determined the differences in the microstructure of meal patterns in rats fed a high fat diet (HF: 38% fat kcal) and in rats pair-fed an isocaloric, isonitrogenous low fat diet (LF: 10% fat kcal) and changes in meal patterns measured after long-term maintenance on the HF diet. RESULTS: Rats fed the HF diet had a significant 50% increase in meal frequency compared to rats fed the LF diet; in addition, there was a significant reduction in meal size (32%) and inter meal interval (38%) consistent with induction of satiation. After 8 weeks on the HF diet, these parameters tend to approach those of rats maintained on the LF diet. There was a significant 56% decrease in the activation of neurons in the NTS in response to intragastric gavage of lipid in rats maintained for 8 weeks on the HF compared to LF diet. CONCLUSION: Dietary fat alters meal patterns consistent with induction of a short-term satiety signal. This signal is attenuated with long-term exposure to dietary lipid, in the absence of ingestion of additional calories or changes in body weight. This adaptation of short-term satiety might contribute to diet-induced obesity.     

Endogenous pro-resolving and anti-inflammatory lipid mediators: the new hope of atherosclerotic diseases

Atherosclerosis is a complex disease process in which genetic, lipid, cellular, and immunological factors combine to determine the location, severity, and timing of lesion development and clinical events. It has been demonstrated, however, that inflammation governed atherosclerosis during the course of development of atherosclerosis. It has also been demonstrated to be effective to decrease the cardiovascular events and improve the prognosis of atherosclerotic diseases by regulating inflammatory reaction (e.g., statins). However, endogenous mechanisms of limiting inflammation in atherosclerosis are still unclear. Recent studies showed that lipoxidase/leukotrienes (LOX/LTs) pathway played important role in the ignition and development of atherosclerosis, whereas resolvins (E-series resolvins and D-series resolvins) and protectins [protectin D1 (PD1) and neuroprotectin D1 (NPD1)], endogenous lipid-derived mediators, inhibited inflammation through pro-resolution and counter-modulating immune inflammation reaction in atherosclerosis. Hence, we hypothesize that increased endogenous lipid mediators mentioned above play a vital role in anti-atherosclerosis and plaque stabilization through pro-resolution and anti-inflammation by LOX/LTs pathway. In addition, we predict that the endogenous lipid mediators may be a new target for treatment of atherosclerotic diseases.     

Role for periodontitis in the progression of lipid deposition in an animal model

Epidemiologic studies have implicated periodontitis as a risk factor for the development of cardiovascular disease. However, no prospective studies investigating this potential relationship have been carried out. Age- and sex-matched New Zealand White rabbits were maintained on a diet consisting of 0.5% fat for 13 weeks to induce the accumulation of lipid deposits in the aorta as a model for atherogenesis. One-half of the animals received silk ligatures around their mandibular premolars followed by an application of a periodontal pathogen, Porphyromonas gingivalis, to induce periodontitis. Animals were sacrificed after 14 weeks. Periodontal disease severity was quantified radiographically, histologically, and by direct visualization of bone loss on defleshed skulls. Lipid deposition was evaluated by computer-assisted morphometry in the aortas en face after lipid deposits were stained with Sudan IV. Animals with experimentally induced periodontitis had more extensive accumulations of lipids in the aorta than did nonperiodontitis animals (P < 0.05), and there was a positive correlation between the severity of periodontal disease and the extent of lipid deposition (r(2) = 0.9501). The results provide direct evidence that periodontitis may be a risk factor and may contribute to the pathogenesis of atherosclerosis. The data support the concept that infections at remote locations can modulate atherosclerotic events distantly.     

Primary biliary cirrhosis and coronary atherosclerosis: Protective antioxidant effect of bilirubin

Increased concentration of lipid peroxidation products in patients with primary biliary cirrhosis is related to elevation of serum lipid content, but not to activation of lipid peroxidation. Hyperbilirubinemia in patients with primary biliary cirrhosis is accompanied by a decrease in the concentration of lipid peroxidation products and increase in antioxidant activity of blood serum. Antioxidants play a major role in the prevention of atherosclerosis. We hypothesized that the absence of increased risk of atherosclerosis in patients with primary biliary cirrhosis is due to inhibition of lipid peroxidation in blood serum by antioxidant compound bilirubin. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 23–28, January, 2008     

Translational Mini‐Review Series on Th17 Cells: CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell‐mediated regulation

Atherosclerosis is a chronic inflammatory disease. Immunomodulation of atherosclerosis emerges as a promising approach to prevention and treatment of this widely prevalent disease. The function of high‐density lipoprotein (HDL) to promote reverse cholesterol transport may explain the ability of its protection against atherosclerosis. Findings that HDL and apolipoprotein A‐I (apoA‐I) inhibited the ability of antigen presenting cells (APCs) to stimulate T cells might be attributed to lipid raft, a cholesterol‐rich microdomain exhibiting functional properties depending largely upon its lipid composition. Thus, modulating cholesterol in lipid raft may provide a promising anti‐atherogenic strategy.     

Coronary heart disease, hypercholesterolemia, and atherosclerosis. I. False premises

Lipid-rich caseous debris of advanced lesions stimulated interest in the role of cholesterol and lipids in atherosclerosis. Lipid-containing arterial lesions in cholesterol-overfed animals (cholesterolosis) and xanthomatous vascular lesions in subjects with familial hypercholesterolemia were then misrepresented as being atherosclerotic and led to the development of the hypercholesterolemic/lipid hypothesis. It is untenable that cholesterol, an essential multifunctional metabolite, is pathogenic at all blood levels and hypercholesterolemia is not prerequisite for human or experimental atherosclerosis. Serum cholesterol levels display a poor correlation with atherosclerosis at autopsy and with unreliable national coronary heart disease (CHD) mortality in each sex. Atherosclerosis topography and its iatrogenic production in humans and experimentally in herbivores by hemodynamic means both support a biomechanical causation and preclude causality by any circulating humoral factor. CHD, not a specific disease, is a nonspecific complication of many diseases including atherosclerosis and cannot be equated with coronary atherosclerosis due to differences in pathology and pathogenesis. Thus, extrapolations from CHD risk factors or correlations with fallacious vital statistics to atherosclerosis are invalid. It follows that the hypercholesterolemic/lipid hypothesis evolving from false premises, misuse of CHD, scientific misrepresentation, and fallacious data has no legitimate basis.     

Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition

Dysregulated cholesterol metabolism is a major risk factor for atherosclerosis and other late-onset disorders, such as Alzheimer's disease. The scavenger receptor, class B, type I (SR-BI) is critical in maintaining the homeostasis of cholesterol and alpha-tocopherol. SR-BI binds high-density lipoproteins (HDL) and mediates the selective transfer of cholesteryl esters and alpha-tocopherol from circulating HDL to cells. SR-BI is also involved in reverse cholesterol transport from peripheral tissues into the liver. Previous studies using SR-BI genetic knockout mice indicated that the deletion of SR-BI resulted in an accelerated onset of atherosclerosis. We hypothesized that SR-BI-dependent lipid dysregulation might disrupt brain function leading to cognitive impairment. Here, we report that very old SR-BI knockout mice show deficient synaptic plasticity (long-term potentiation) in the CA1 region of the hippocampus. Very old SR-BI KO mice also display selective impairments in recognition memory and spatial memory. Thus, SR-BI influences neural and cognitive processes, a finding that highlights the contribution of cholesterol and alpha-tocopherol homeostasis in proper cognitive function.     

Coronary endarterectomy: the long-term local effects

The chronic effects of manual endarterectomy of coronary arteries are described. Nine male patients (age, 58-70 years) had undergone right coronary endarterectomy and bypass grafting 6-9 years prior to death and autopsy. One of the nine endarterectomized arteries had thrombosed soon after the procedure, while the other eight had maintained blood flow for up to eight years. These patent arteries had variable myofibrointimal proliferation ranging from mild to marked, the latter with significant stenosis. Recurrent atherosclerosis was present focally in two endarterectomized arteries. Death had occurred from causes unrelated to pathology in the endarterectomized vessels and provided a unique opportunity to assess the variable long-term effects of this form of arterial injury.     

Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice

This is an overview of recent findings, mainly from our laboratory, describing the cardiovascular functional phenotypes and pharmacological responses in mice genetically deficient in apolipoprotein E (apoE-KO). ApoE-KO mice are hyperlipidemic and spontaneously develop atherosclerosis. We have detected several new cardiovascular functional phenotypes in apoE-KO mice: hyperglycemia, age-dependent aortic stiffening, cardiac hypertrophy and increased cardiac output. Angiotensin II (Ang II) promoted vascular inflammation and atherosclerosis, increased vascular stiffness, and induced abdominal aortic aneurysm (AAA) in apoE-KO mice, in which activation of NF-kappaB mediated pro-inflammatory genes plays an important role. Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) significantly inhibited NO-mediated vascular responses and accelerated atherosclerosis in apoE-KO mice, supporting a protective role of NO against atherosclerosis. Estrogen attenuated atherosclerosis in apoE-KO mice, even in those with atherosclerosis being accelerated by Ang II, hyperglycemia, or L-NAME, demonstrating an anti-atherosclerotic effect of estrogen. Simvastatin paradoxically increased lipid and atherosclerosis in apoE-KO mice, but it decreased lipid and atherosclerosis in LDLR-KO mice, indicating that anti-atherosclerotic effect of simvastatin requires the presence of an intact apoE.