二甲双胍通过激活AMPK/STAT3通路调控巨噬细胞分化抑制小鼠动脉粥样硬化形成

目的 探究二甲双胍(Met)通过腺苷酸活化蛋白激酶(AMPK)/信号转导及转录激活因子3(STAT3)信号通路调控巨噬细胞表型对小鼠动脉粥样硬化(As)形成的影响。方法 体外培养RAW264.7巨噬细胞,使用脂多糖促进巨噬细胞分化,同时使用Met刺激细胞。流式细胞术检测不同表型(CD86、CD206)巨噬细胞比例。Western blot检测相关信号通路蛋白诱导型一氧化氮合酶(iNOS)、精氨酸酶1(Arg-1)、AMPK、磷酸化AMPK(pAMPK)、STAT3、磷酸化STAT3(pSTAT3)蛋白表达水平。高脂饲料喂养ApoE－/－小鼠构建As模型。实验组(Met组)小鼠予Met灌胃干预,对照组(CTL组)小鼠给予同体积生理盐水灌胃干预。3个月后,提取小鼠大动脉全长(头臂干至双侧髂动脉)及主动脉根部,分别行油红O染色和免疫荧光染色,评价主动脉脂质沉积情况和脂质斑块内巨噬细胞不同表型比例。提取大动脉蛋白,Western blot验证相关信号通路的AMPK、pAMPK、STAT3、pSTAT3蛋白表达水平。结果 细胞实验表明,Met刺激后M1巨噬细胞比例明显减少,M2巨噬细胞比例明显增加(P＜0.05),AMPK活性明显增加,而STAT3活性明显下降。动物实验表明,在造模3个月后,油红O染色示Met组小鼠大动脉全长和主动脉瓣膜处脂质沉积均较CTL组明显减少(P＜0.05)；免疫荧光染色示Met组脂质斑块内M1巨噬细胞比例较CTL组明显减少,而M2巨噬细胞比例较CTL组明显增多(P＜0.05)。Western blot实验显示,与CTL组相比,Met组AMPK活性明显增加,而STAT3活性明显降低(P＜0.05)。结论 Met通过激活AMPK抑制STAT3活性,调控斑块内巨噬细胞表型分化,抑制小鼠As形成。     

Animal models to evaluate anti‐atherosclerotic drugs

Atherosclerosis is a multifactorial condition characterized by endothelial injury, fatty streak deposition, and stiffening of the blood vessels. The pathogenesis is complex and mediated by adhesion molecules, inflammatory cells, and smooth muscle cells. Statins have been the major drugs in treating hypercholesterolemia for the past two decades despite little efficacy. There is an urgent need for new drugs that can replace statins or combined with statins. The preclinical studies evaluating atherosclerosis require an ideal animal model which resembles the disease condition, but there is no single animal model which mimics the disease. The animal models used are rabbits, rats, mice, hamsters, mini pigs, etc. Each animal model has its own advantages and disadvantages. The method of induction of atherosclerosis includes diet, chemical induction, mechanically induced injuries, and genetically manipulated animal models. This review mainly focuses on the various animal models, method of induction, the advantages, disadvantages, and the current perspectives with regard to preclinical studies on atherosclerosis.     

Association between Bacterial Infection and Peripheral Vascular Disease: A Review

There are an increasing number of data showing a clinically important association between bacterial infection and peripheral artery disease (PAD). Bacteria suspected of being involved in PAD pathogenesis are: periodontal bacteria, gut microbiota, Helicobacter pylori, and Chlamydia pneumoniae. Infectious agents may be involved in the pathogenesis of atherosclerosis via activation of a systemic or local host immunological response to contamination of extravascular tissues or the vascular wall, respectively. A systemic immunological reaction may damage vascular walls in the course of autoimmunological cross-reactions between anti-pathogen antibodies and host vascular antigens (immunological mimicry), pathogen burden mechanisms (nonspecific activation of inflammatory processes in the vascular wall), and neuroendocrine-immune cross-talk. Besides activating the inflammatory pathway, bacterial infection may trigger PAD progression or exacerbation by enhancement of platelet reactivity, by a stimulatory effect on von Willebrand factor binding, factor VIII, fibrinogen, P-selectin activation, disturbances in plasma lipids, increase in oxidative stress, and resistance to insulin. Local inflammatory host reaction and induction of atherosclerotic plaque progression and/or instability result mainly from atherosclerotic plaque colonization by microorganisms. Despite these premises, the role of bacterial infection in PAD pathogenesis should still be recognized as controversial, and randomized, controlled trials are required to evaluate the outcome of periodontal or gut bacteria modification (through diet, prebiotics, and probiotics) or eradication (using antibiotics) in hard and surrogate cardiovascular endpoints.     

Pseudo subclavian steal syndrome: Case report

IntroductionVertebrobasilar insufficiency (VBI) is a condition that results from restricted blood flow to the posterior portions of the brain, which are primarily served by the vertebral and basilar arteries. It is the most common cause of vertigo in the elderly and is usually accompanied by impaired vision and sensation. Congenital abnormalities, atherosclerosis, stroke and/or trauma may all lead to decreased vertebrobasilar circulation. A syndrome called Subclavian Steal Syndrome (SSS), which manifests with similar neurological symptoms but with a different pathophysiology, may also cause VBI.Case presentationA middle-aged female presented with gradual onset fainting and vertigo attacks. Cardiac, auditory and autonomic etiologies were investigated and excluded. Clinical findings and presentation were highly suggestive of subclavian steal. However, subsequent CT angiography showed normal subclavian arteries. Instead, findings included a persistent right trigeminal artery (PTA), stenosis of the right proximal internal carotid artery, atresis of the left vertebral artery and distal segment of right vertebral artery, congenitally compromised changes in vertebral circulation (bilateral absence of the posterior communicating arteries (PCOMs)) and an absent anterograde vertebrobasilar circulation. Symptoms resolved after carotid endarterectomy.DiscussionDue to the absence of a normally developed posterior circulation, the PTA was the main source of blood supply for the patient. Development of recent artheromatous changes in the right internal carotid artery, however, resulted in decreased blood through PTA, further compromising posterior circulation. This resulted in vertebrobasilar insufficiency, and manifested in symptomology similar to SSS.ConclusionsThis clinical encounter illustrates the relative contribution of anatomical and vasoocclusive factors in closely mimicking symptoms of subclavian steal syndrome.     

Cardiovascular morbidity and mortality after kidney transplantation

Kidney transplantation is the optimal treatment for patients with end stage renal disease (ESRD) who would otherwise require dialysis. Patients with ESRD are at dramatically increased cardiovascular (CV) risk compared with the general population. As well as improving quality of life, successful transplantation accords major benefits by reducing CV risk in these patients. Worldwide, cardiovascular disease remains the leading cause of death with a functioning graft and therefore is a leading cause of graft failure. This review focuses on the mechanisms underpinning excess CV morbidity and mortality and current evidence for improving CV risk in kidney transplant recipients. Conventional CV risk factors such as hypertension, diabetes mellitus, dyslipidaemia and pre‐existing ischaemic heart disease are all highly prevalent in this group. In addition, kidney transplant recipients exhibit a number of risk factors associated with pre‐existing renal disease. Furthermore, complications specific to transplantation may ensue including reduced graft function, side effects of immunosuppression and post‐transplantation diabetes mellitus. Strategies to improve CV outcomes post‐transplantation may include pharmacological intervention including lipid‐lowering or antihypertensive therapy, optimization of graft function, lifestyle intervention and personalizing immunosuppression to the individual patients risk profile.     

Antibodies to periodontal pathogens and coronary artery calcification in type 1 diabetic and nondiabetic subjects

Background and Objective:  The aim of this study was to examine whether serum immunoglobulin G (IgG) levels to Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans are higher in type 1 diabetic patients than in controls and are associated with coronary artery calcification, a measure of atherosclerosis.
Material and Methods:  One-hundred and ninety nine type 1 diabetic patients (mean age 38 ± 4 years) and 201 age- and gender-matched nondiabetic subjects had coronary artery calcification, as measured by electron beam computed tomography. Serum IgG levels to P. gingivalis W50 and to A. actinomycetemcomitans HK1651 whole cells were measured by enzyme-linked immunosorbent assay.
Results:  A similar proportion of diabetic patients (29%) and controls (31%, p  = 0.7) had elevated serum IgG to periodontal bacteria, defined as being above the median antibody level for both microorganisms. Elevated antibody levels were associated with higher systolic blood pressure ( p  = 0.02) and an increased odds of coronary artery calcification in all subjects combined (odds ratio = 1.7, p  = 0.047) and in diabetic subjects examined separately (odds ratio = 2.01, p  = 0.027). Association of serum IgG levels with coronary artery calcification was independent of social class, lipids and antibody levels to other microorganisms, but not systolic blood pressure (odds ratio = 1.4, p  = 0.1 on adjustment for blood pressure). There was no association between serum IgG level and vascular endothelial function.
Conclusion:  Elevated levels of serum IgG to P. gingivalis and A. actinomycetemcomitans are associated with coronary artery atherosclerosis. This may reflect a direct role for periodontal infection or a role for the host response to infection in coronary atherosclerosis, particularly in patients with type 1 diabetes.     

Metabolic syndrome: pathogenesis, medical care and dental implications

BACKGROUND: The dental literature contains little information about metabolic syndrome (MetS) and its dental implications. TYPES OF STUDIES REVIEWED: The authors conducted a MEDLINE search for the period 2000 through 2005, using the term "metabolic syndrome" to define its pathophysiology, medical treatment and dental implications. RESULTS: MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke. CLINICAL IMPLICATIONS: Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis.     

Review: Pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways

A hallmark of infection with the gram‐negative pathogen Porphyromonas gingivalis is the induction of a chronic inflammatory response. P. gingivalis induces a local chronic inflammatory response that results in oral inflammatory bone destruction, which manifests as periodontal disease. In addition to chronic inflammation at the initial site of infection, mounting evidence has accumulated supporting a role for P. gingivalis‐mediated periodontal disease as a risk factor for several systemic diseases including, diabetes, preterm birth, stroke, and atherosclerotic cardiovascular disease. A growing number of in vitro studies have demonstrated that P. gingivalis infection stimulates cell activation commensurate with expected responses paralleling inflammatory atherosclerotic‐type responses. Furthermore, various mouse models have been used to examine the ability of P. gingivalis to stimulate chronic inflammatory plaque accumulation and recent studies have pointed to a pivotal role for innate immune signaling via the Toll‐like receptors in the chronic inflammation associated with P. gingivalis infection. In this review we discuss the pathogen and host cell specificity of these responses and discuss possible mechanisms by which this oral pathogen can induce and maintain a chronic state of inflammation at sites distant from oral infection.     

脑小血管病亚型和颅外颈动脉硬化与血管性认知障碍的相关性研究

目的： 研究脑小血管病（cerebral small vessel disease,CSVD）亚型与颅外颈动脉粥样硬化及血管性认知障碍（vascular cognitive impairment,VCI）的相关性。 方法： 收集200例无卒中CSVD患者的人口学、用药等资料,行颈动脉超声并使用颅外颈动脉硬化评分评估颈动脉粥样硬化程度,行头颅磁共振（magnetic resonance imaging,MRI）并评估各类CSVD亚型病变程度。采用蒙特利尔认知评估量表（Montreal cognitive assessment,MoCA）筛查认知功能异常患者,根据MoCA总分<23分将患者分成VCI组和无VCI组。采用单因素分析和多因素logistic回归筛选无卒中患者VCI的独立危险因素。建立模型并使用受试者工作特征曲线（receiver operating characteristic,ROC）评估独立危险因素,计算临界值等。根据独立危险因素中的CSVD评分最佳界值计算脑小血管性认知负荷评分并使用ROC曲线评估。 结果： Logistic回归分析得出腔隙性脑梗死（lacunar infarction,LI）+腔隙灶个数之和、Fazekas评分、全脑皮层萎缩（global cortical atrophy,GCA）评分与VCI显著正相关（P<0.05）,颅外颈动脉硬化评分与VCI无明显相关性（P>0.05）;所建立预测模型和脑小血管性认知负荷评分曲线下面积（area under the curve,AUC）>0.7。 结论： 部分CSVD亚型与VCI存在明显相关性,颅外轻度颈动脉粥样硬化与VCI无明显相关性;可通过CSVD建立模型或使用临床更方便的脑小血管性认知负荷评分筛查无卒中患者的小血管性认知障碍。