The metabolic syndrome and vascular disease in Asia

The metabolic syndrome is a constellation of vascular disease risk factors that includes hyperglycaemia, hypertension, and dyslipidaemia, which are largely mediated by accumulating fat depots, particularly when centrally deposited. Increasing adiposity promotes insulin resistance, low grade inflammation and endothelial dysfunction, which promote the development of atherogenic vascular disease. Increases in percentage body fat result from a number of parameters, including ageing, and changes in lifestyle factors that promote a metabolic imbalance, such as decreasing physical activity and adverse dietary patterns. As Asian populations continue to modernize, levels of physical activity are declining as home and workplace jobs become more automated and sedentary and transportation more readily available. Similarly, dietary changes are introduced, with healthy traditional plant-based diets being replaced by cheaper calorie dense high fat foods. These changes are resulting in rapid increases in the prevalence of obesity throughout Asia, and the subsequent development of the metabolic syndrome. To minimise further development of the obesity pandemic and subsequent vascular disease, innovative population-based preventative lifestyle and therapeutic strategies interventions need to be introduced.     

Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome

In animal experiments, the potent antioxidant and free radical scavenger alpha-lipoic acid has been shown to cause weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, as well as to lower blood pressure, all of these being components of the metabolic syndrome. Recent investigations on its mechanisms of action indicate that alpha-lipoic acid can affect central and peripheral modulation of 5'-AMP-activated protein kinase, activate PPAR-alpha and PPAR-gamma, modulate PPAR-regulated genes and upregulate the expression of PPAR-gamma mRNA and protein in cardiac tissue and aorta smooth muscle. To a large extent, these findings can explain the observed beneficial metabolic effects of alpha-lipoic acid, supporting its potential application as a therapeutic agent for the treatment of the metabolic syndrome.     

Molecular and cellular mechanisms in the pathophysiology of severe head injury

The pathophysiological process following traumatic brain injury is extremely complex and not fully understood. Recent developments have further advanced our knowledge of the cellular and molecular mechanisms that cause this damage. The excitotoxic damage, alterations in calcium homeostasis and free radical induced damage are thought to be the key pathways in this process. It is believed that the final target of all these pathways is the mitochondria, through the alteration in the mitochondrial permeability transition pore. Moreover, the inflammatory response may be important in the exacerbation of secondary damage but its exact role is not very well known. Further advances in our understanding of the cellular and molecular mechanisms will be crucial in the design of new therapies that should improve the prognosis of the traumatic brain injury patients.     

Non-steroidal anti-inflammatory drugs attenuate the vascular responses in aging metabolic syndrome rats

Aim:

Metabolic syndrome (MS) and aging are low-grade systemic inflammatory conditions, and inflammation is a key component of endothelial dysfunction. The aim of this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) upon the vascular reactivity in aging MS rats.

Methods:

MS was induced in young male rats by adding 30% sucrose in drinking water over 6, 12, and 18 months. When the treatment was finished, the blood samples were collected, and aortas were dissected out. The expression of COX isoenzymes and PLA₂ in the aortas was analyzed using Western blot analysis. The contractile responses of aortic rings to norepinephrine (1 μmol/L) were measured in the presence or absence of different NSAIDs (10 μmol/L for each).

Results:

Serum levels of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in control rats were remained stable during the aging process, whereas serum IL-6 in MS rats were significantly increased at 12 and 18 months. The levels of COX isoenzyme and PLA₂ in aortas from control rats increased with the aging, whereas those in aortas from MS rats were irregularly increased with the highest levels at 6 months. Pretreatment with acetylsalicylic acid (a COX-1 preferential inhibitor), indomethacin (a non-selective COX inhibitor) or meloxicam (a COX-2 preferential inhibitor) decreased NE-induced contractions of aortic rings from MS rats at all the ages, with meloxicam being the most potent. Acetylsalicylic acid also significantly reduced the maximum responses of ACh-induced vasorelaxation of aortic rings from MS rats, but indomethacin and meloxicam had no effect.

Conclusion:

NSAIDs can directly affect vascular responses in aging MS rats. Understanding the effects of NSAIDs on blood vessels may improve the treatment of cardiovascular diseases and MS in the elders.     

Pharmacotherapy for the metabolic syndrome

The Metabolic Syndrome (MetS) confers a greater risk for both diabetes and cardiovascular diseases. Both insulin resistance and low grade inflammation appear to be pivotal in the pathogenesis of this disorder. The cornerstone of treatment presently is therapeutic lifestyle change with the emphasis on weight loss by diet and exercise. It appears that the evidence base will support statins as first line therapy for the dyslipidemia. Also, there is a limited role for both bile acid sequestrants and fibrates in certain subgroup of patients. It would appear that the Angiotensin converting enzyme inhibitors (ACEs) and angiotensin II receptor blockers (ARBs) are the preferred therapies for hypertension but invariably a combination therapy with additional drugs is required keeping in mind that certain drugs can exacerbate the dyslipidemia and or glycemia of MetS. Whilst metformin appears to be the drug of choice for the dysglycemia, thiazolidinediones (TZDs) like pioglitazone can also be beneficial but recent concern about bladder cancer has resulted in its discontinuation in certain countries in Europe. Metformin therapy has been shown to prevent new onset MetS. Modulating the incretin axis can prove very fruitful. A drug targeting all 3 disorders would be ideal but to date does not exist.     

Characterization of vascular complications in experimental model of fructose-induced metabolic syndrome

Vascular dysfunction is an important complication associated with metabolic syndrome (MS). Here we fully characterized vascular complications in a rat model of fructose-induced MS. MS was induced by adding fructose (10%) to drinking water to male Wistar rats of 6 weeks age. Blood pressure (BP) and isolated aorta responses phenylephrine (PE), KCl, acetylcholine (ACh), and sodium nitroprusside (SNP) were recorded after 6, 9, and 12 weeks of fructose administration. In addition, serum levels of glucose, insulin, uric acid, tumor necrosis factor α (TNFα), lipids, advanced glycation end products (AGEs), and arginase activity were determined. Furthermore, aortic reactive oxygen species (ROS) generation, hemeoxygenase-1 expression, and collagen deposition were examined. Fructose administration resulted in a significant hyperinslinemia after 6 weeks which continued for 12 weeks. It was also associated with a significant increase in BP after 6 weeks which was stable for 12 weeks. Aorta isolated from MS animals showed exaggerated contractility to PE and KCl and impaired relaxation to ACh compared with control after 6 weeks which were clearer at 12 weeks of fructose administration. In addition, MS animals showed significant increases in serum levels of lipids, uric acid, AGEs, TNFα, and arginase enzyme activity after 12 weeks of fructose administration. Furthermore, aortae isolated from MS animals were characterized by increased ROS generation and collagen deposition. In conclusion, adding fructose (10%) to drinking water produces a model of MS with vascular complications after 12 weeks that are characterized by insulin resistance, hypertension, disturbed vascular reactivity and structure, hyperuricemia, dyslipidemia, and low-grade inflammation.     

Cellular and molecular mechanisms of vascular injury in diabetes--part II: cellular mechanisms and therapeutic targets

Although the mechanisms by which insulin-resistance and hyperglycemia lead to cardiovascular disease are still incompletely understood, all mechanisms apparently converge on the vessel wall and the endothelium as a common disease target. Endothelial cells play a crucial role in vascular homeostasis, providing a functional barrier and modulating several signals involved in vasomotion, as well as antiplatelet, anti-inflammatory, anti-proliferative, and anti-oxidant properties of the vessel wall. Endothelial cell dysfunction occurs early in diabetes and insulin resistance states. Since atherosclerosis may result from an imbalance between the magnitude of vascular injury and the capacity of repair, a role has been recently postulated for a defective mobilization of vascular progenitors, including endothelial progenitor cells, in the pathogenesis of vascular disease. Here we summarize the evidence for such an occurrence. We also here highlight how new insights into pathways of vascular damage in diabetes may indicate new targets for preventive and treatment strategies.     

Cellular and molecular mechanisms of vascular injury in diabetes--part I: pathways of vascular disease in diabetes

Diabetes-induced micro- and macrovascular complications are the major causes of morbidity and mortality in diabetic patients. While hyperglycemia is a key factor for the pathogenesis of diabetic microvascular complications, it is only one of the multiple factors capable of increasing the risk of macrovascular complications. Hyperglycemia induces vascular damage probably through a single common pathway - increased intracellular oxidative stress - linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways. In addition, in conditions of insulin resistance, i.e., preceding the onset of type 2 diabetes, the phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway is selectively inhibited, while the mitogen activated protein (MAP)-kinase pathway remains largely unaffected, thus allowing compensatory hyperinsulinemia to elicit pro-atherogenic events in vascular smooth muscle and endothelial cells, including increased cell proliferation, and the expression of plasminogen activator inhibitor-1, as well as of proinflammatory cytokines and endothelial adhesion molecules.     

Molecular mechanisms for drug interactions with hERG that cause long QT syndrome

The human ether-a-go-go-related gene (hERG) encodes the pore-forming alpha-subunit of a voltage-gated potassium (K(+)) channel. A variety of unrelated compounds reduce K(+ )current in the heart by blocking the pore or disrupting trafficking of the hERG channel to the membrane surface. This induces a syndrome known as long QT, which arises from abnormalities in action potential repolarisation and can degenerate into lethal cardiac arrhythmias. As a result, this undesirable side effect has severely hindered safe drug development. This review describes progress in understanding the molecular basis for drug binding to hERG, outlines the characteristics of hERG ligands and discusses experimental and in silico approaches for identifying compounds with QT liabilities. Recent developments should enable recognition of hERG-positive compounds at the early stages of their development.     

代谢综合征患者血栓前状态与血管内皮功能的关系

目的探讨代谢综合征（MS）患者血栓前状态、血管内皮功能损伤情况及两者间的关系。方法选择127例MS患者（MS组）及正常健康人20例（对照组）。MS组患者根据有无颈动脉斑块又分为2组,Ⅰ亚组（无斑块）68例,Ⅱ亚组（有斑块）59例。采用高分辨率超声技术检测颈动脉内膜中层厚度（IMT）,并分别测定凝血酶原时间（PT）、部分凝血活酶时间（APTT）、凝血酶时间（TT）、纤维蛋白原（FIB）、D二-聚体水平,并进行比较。结果与Ⅰ亚组和对照组比较,Ⅱ亚组IMT显著增大,PT、APTT及TT水平均缩短,FIB及D二-聚体水平明显升高,差异均有统计学意义（P〈0.05）。Ⅰ亚组除FIB和D二-聚体水平高于对照组（P〈0.05）外,其余指标比较,差异均无统计学意义（P〉0.05）。结论早期检测血管内皮功能及是否存在血栓前状态,对于改善MS患者预后至关重要。     

代谢综合征患者血栓前状态与血管内皮功能的关系

目的 探讨代谢综合征(MS)患者血栓前状态、血管内皮功能损伤情况及两者间的关系.方法 选择127例MS患者(MS组)及正常健康人20例(对照组).MS组患者根据有无颈动脉斑块又分为2组,Ⅰ亚组(无斑块)68例,Ⅱ亚组(有斑块)59例.采用高分辨率超声技术检测颈动脉内膜中层厚度(IMT),并分别测定凝血酶原时间(PT)、部分凝血活酶时间(APTT)、凝血酶时间(TT)、纤维蛋白原(FIB)、D-二聚体水平,并进行比较.结果 与Ⅰ亚组和对照组比较,Ⅱ亚组IMT显著增大,PT、APTT及TT水平均缩短,FIB及D-二聚体水平明显升高,差异均有统计学意义(P<0.05).Ⅰ亚组除FIB和D-二聚体水平高于对照组(P<0.05)外,其余指标比较,差异均无统计学意义(P>0.05).结论 早期检测血管内皮功能及是否存在血栓前状态,对于改善MS患者预后至关重要.     

Hypolipidemic therapy for the metabolic syndrome

The metabolic syndrome appears to affect a significant proportion of the population and is associated with increased risk for development of cardiovascular disease as well as of type-2 diabetes. No single treatment for the metabolic syndrome as a whole yet exists. While the primary management of patients with the metabolic syndrome involves healthy lifestyle promotion, the atherogenic dyslipidemia is a primary target for cardiovascular disease risk reduction in these patients. Statin therapy provides effective reduction of LDL-cholesterol, which represents the primary therapeutic goal of lipid-lowering therapy in patients at risk for cardiovascular disease. Fibrates in turn are effective in normalizing lipid levels (mainly triglycerides and HDL-cholesterol) in patients with the metabolic syndrome and may improve insulin resistance. Whereas statins remain the drug of choice for patients who need to achieve the LDL-cholesterol goal, fibrate therapy may represent an alternative for those with low HDL-cholesterol and high triglyceride levels. The simultaneous use of fibrates could be indicated in patients whose LDL-cholesterol is controlled by statin therapy but whose HDL-cholesterol and/or triglycerides are still inappropriate. Such a combination, however, needs careful monitoring due to the potential hazard of adverse drug interactions. Nicotinic acid and ezetimibe may be useful agents for therapy, particularly when combined with statins. A number of emerging therapies offer potential as future options for the pharmacological treatment of metabolic syndrome.     

代谢综合征对皮质下缺血性血管病认知功能的影响

目的探讨代谢综合征（Mets）对皮质下缺血性血管病（SIVD）认知功能的影响。方法选择226例SIVD患者,其中Mets患者104例,代谢综合征倾向（R-Mets）68例,非代谢综合征（No-Mets）54例。Mets的诊断标准采用NCEP-ATPⅢ标准;应用简易智能精神状态量表（MMSE）、剑桥老年认知量表中文版（CAMCOG-C）对SIVD患者的认知功能进行评定;采用Blennow量表,按照脑损害程度分为4个亚型（Ⅰ～Ⅳ型,0～3分）。结果 Mets组和R-Mets组MMSE、CAMCOG-C均显著低于No-Mets组（均P〈0.05）;Mets组CAMCOG-C显著低于R-Mets（P〈0.05）。腰围、空腹血糖（IGT）、收缩压（SBP）、舒张压（DBP）、甘油三酯（TG）与SIVD患者总体认知得分呈显著负相关（均P〈0.05）;HDL-C与MMSE、CAMCOG-C得分呈显著正相关（均P〈0.05）。No-Mets组中Ⅰ、Ⅱ型所占比例较高,分别为51.6%、27.8%,R-Mets组和Mets合并组中Ⅲ、Ⅳ型所占比例较高,分别为36%、30.8%,No-Mets组与R-Mets组和Mets合并组Ⅰ、Ⅱ、Ⅲ、Ⅳ各亚型发生率比较均有统计学意义（均P〈0.05）。结论 Mets及其各因子加重SIVD认知损害,其中腹型肥胖、IGT、SBP、DBP、TG、HDL-C是其重要危险因素;随着RMets、Mets发生率增高,SIVD脑损害愈加明显。     

Hypercoagulability in the metabolic syndrome

The metabolic syndrome is characterized by a combination of obesity, chronic inflammation and insulin resistance. This syndrome also has features of a hypercoagulable state, consisting of increased levels of clotting factors (tissue factor, factor VII and fibrinogen) as well as inhibition of the fibrinolytic pathway (increased plasminogen activator inhibitor-1 and decreased tissue plasminogen activator activity). Simultaneously, the presence of endothelial dysfunction and dyslipidemia triggers platelet aggregability, thus further increasing the risk of thrombotic events both in the arterial and venous system. Although mechanisms of coagulation activation are well described for other diseases, the precise etiology is not well known in the metabolic syndrome. Thus far, only obesity has been shown to be a modest risk factor for venous thromboembolic events, whereas accurate data for metabolic syndrome patients are lacking. Hence, routine interventions for prevention of venous thromboembolism are not yet warranted. However, as dyslipidemia is associated with procoagulant changes, this could be a possible target for therapeutic intervention. In view of the rising incidence of metabolic syndrome even at a young age, both the incidence of venous thromboembolism and the effect of intervention on markers of hypercoagulability in metabolic syndrome call for further studies.     

Molecular mechanisms and therapeutic strategies of chronic renal injury: role of rho-kinase in the development of renal injury

Rho/Rho-kinase plays an important role not only in the vasoconstrictor mechanism but also in cellular morphology, motility, adhesion, and proliferation. This pathway also serves to modulate the structure and function of various kidney cells including tubular epithelial cells, mesangial cells, and podocytes. The inhibition of the Rho/Rho-kinase pathway elicits marked increases in renal blood flow in vivo and dilates both afferent and efferent arterioles preconstricted by angiotensin II in vitro. In renal injury, intrarenal angiotensin II is reported to be activated, which subsequently would upregulate the Rho-kinase pathway. A selective Rho-kinase inhibitor, fasudil, has recently been shown to improve renal damage resulting from hypertensive glomerulosclerosis, unilateral ureteral obstruction (for interstitial renal fibrosis) and subtotal nephrectomy. Of interest, fasudil upregulated the expression of p27(kip1), a cyclin-dependent kinase inhibitor, and increased the p27(kip1) immuno-positive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry. Collectively, the Rho-kinase pathway is involved in the pathogenesis of renal injury. Clinical application of this type of therapy however awaits further investigations.     

Molecular mechanisms of paraquat-induced acute lung injury: a current review

Abstract

Paraquat is an organic heterocyclic herbicide that is widely used in agriculture, especially in Asian countries. The prevalence of paraquat poisonings has increased dramatically in the past two decades in China. Nearly all paraquat poisonings resulted from intentional or accidental oral administration leading to acute lung injury and, ultimately, acute respiratory distress syndrome. The mortality rate has been reported to be greater than 90%. However, the exact toxic mechanism remains unclear. Herein, we reviewed and summarized the most recent publications related to the molecular mechanisms of paraquat-induced acute lung injury.     

前列腺素E_1干预大鼠血管球囊损伤后再狭窄的机制探讨

目的观察前列腺素E1(PGE1)在大鼠血管球囊损伤术后对血小板颗粒膜蛋白(GMP140)、D二聚体(Ddimer)、血浆内皮素(ET)及炎性细胞因子白介素1β(IL1β)、白介素6(IL6)、肿瘤坏死因子(TNFα)水平的影响,探讨PGE1对血管球囊损伤术后再狭窄形成的防治机制。方法采用大鼠腹主动脉球囊损伤模型,用药组术前连续5d经尾静脉给予PGE1(8、24、72μg·kg-1),模型组及假手术组给予等容积NS。各组动物于术后6h、24h、10d、21d4个时间点取血,采用酶连免疫吸附试验双抗体夹心法测定血浆中GMP140、Ddimer的含量;采用平衡法测定血浆中内皮素及血清中IL1β、IL6、TNFα的含量。结果与假手术组比球囊损伤模型组术后6h血浆GMP140、Ddimer含量明显升高(P<0.01),PGE1(8、24、72μg·kg-1)各组血浆GMPI40和D二聚体的含量显著降低(P<0.01)。模型组血浆ET含量6h开始增加,24h达高峰,10d降至正常。PGE1(24、72μg·kg-1)两组能明显降低6、24h血浆ET含量(P<0.01)。血管球囊损伤术后6h,模型组TNFα含量达高峰,而IL1β、IL6则在术后24h达高峰,PGE1各组均可在高峰时显著降低IL1β、IL6、TNFα的含量,与模型组相比差异显著(P<0.01),并呈良好的剂量相关性(r=0.747,0.907,0.747)。结论PGE1在大鼠血管球囊损伤术后可降低GMP140、Ddimer及血浆中ET、血清中IL1β、IL6、TNF浕水平的作用,是其干预血管再狭窄形成的重要机制。