Oxidative stress and endothelial dysfunction in vascular disease

In response to physiologic stimuli, endothelial cells dynamically regulate arterial vascular tone by producing vasodilators and vasoconstrictors. Risk factors for atherosclerosis, such as diabetes, smoking, hypercholesterolemia, and hypertension, interfere with this response, promoting endothelial dysfunction and atherosclerosis. This review explores whether oxidative stress might be a common feature of both endothelial dysfunction and atherosclerosis. Using biomarkers to assess endothelial function might provide insights into the pathways for oxidative stress in vascular disease. However, currently available markers of oxidative stress and endothelial function are unsuitable for routine clinical use because they are too expensive and inadequately validated. Thus, there is a need to develop and validate new markers that could be used to both measure oxidative stress and monitor therapies that specifically interrupt oxidative pathways in vascular tissue. Such markers might eventually help to identify susceptible individuals at a stage when cardiovascular complications could be prevented.     

Oxidative stress and endothelial dysfunction in heart failure

The clinical syndrome of congestive heart failure (CHF) is characterized by abnormalities of left ventricular function and neurohormonal regulation, which are accompanied by effort intolerance, fluid retention, and decreased longevity. While an increased sympathetic tone and an activated renin-angiotensin system may contribute to the reduced vasodilatory capacity in patients with CHF, the important role of the endothelium in coordinating tissue perfusion has now been recognized. CHF is associated with endothelial dysfunction, as demonstrated by impaired endothelium-mediated vasodilation. Endothelial dysfunction in patients with CHF is a critical component in the systemic vasoconstriction and reduced peripheral perfusion that characterizes these patients. Endothelial regulation of vascular tone is mediated mainly by nitric oxide. Increased oxidative stress in patients with CHF is likely caused by decreased bioavailability of nitric oxide due to reduced expression of endothelial nitric oxide synthase and increased generation of reactive oxygen species. These react with nitric oxide in the setting of decreased antioxidant defenses that would normally clear these radicals, culminating in attenuated endothelium-dependent vasodilation in patients with CHF. Therapies that improve endothelial function have been shown to improve exercise tolerance and outcomes in patients with CHF. Endothelial dysfunction is thus an important target for future therapy in patients with CHF.     

Clinical implications of endothelial dysfunction

Endothelial dysfunction is increasingly recognized as an early event in the pathogenesis of cardiovascular disease. This observation is consistent with the growing appreciation of the role of endothelium in maintaining cardiovascular health. Endothelial dysfunction and coronary artery disease are both linked to hypertension, hypercholesterolemia, diabetes mellitus, and cigarette smoking. Modification of these conditions improves both endothelial function and coronary artery disease outcomes. Dietary and lifestyle modifications and antioxidant vitamin supplementation have a beneficial effect on endothelial function, as do angiotensin-converting enzyme inhibitors and lipid-lowering agents. Future studies will determine whether interventions that specifically target endothelial dysfunction can reduce rates of clinical disease.     

不同尿酸浓度与氧化应激和内皮损伤指标研究

目的 观察不同血尿酸浓度下氧化应激指标变化,探讨高尿酸引起血管内皮功能损伤的机制.方法 选择男性正常血尿酸及高尿酸血症病例,根据血尿酸值分为5组,每组50例左右,分别测定血浆丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH·Px)、NO、纤溶酶原激活抑制剂-1(PAI-1)、内皮素-1(ET-1)及各项生化指标.结果 尿酸≥380 μmol/L时,MDA、SOD、GSH-Px、PM-1、ET-1均明显增加,NO明显下降(P值均<0.05),但当尿酸≥420 μmol/L时,SOD、GSH-Px明显下降;回归分析显示PAI-1与MDA、尿酸、HOMA胰岛素抵抗指数(HOMA-IR)、TG正相关,与SOD、NO负相关(t=-3.64～6.08,P<0.05);ET-1与MDA、尿酸、HOMA-IR正相关,与NO、GSH-Px、SOD负相关(t=-4.75～6.35,P<0.05).结论 男性血尿酸超过380 umol/L时引起氧化应激,氧化应激、血尿酸、胰岛素抵抗参与了内皮功能紊乱的形成.     

氧化应激与血管内皮功能异常

氧化应激和人体内抗氧化系统功能处于动态平衡之中,如果抗氧化系统不能消除氧化应激,就会产生氧化损伤,导致内皮功能障碍.本文综述氧化应激的产生及其在内皮功能异常中的作用、抗氧化治疗的措施及可能机制.     

Clinical importance of coronary endothelial vasodilator dysfunction and therapeutic options

The vascular endothelium plays a key role in the control of vasomotor tone, local haemostasis and vascular wall proliferation processes. These responses are mediated by a variety of substances released from the endothelium in response to physiological stimuli, including prostacyclin, endothelin, and most importantly nitric oxide (NO). NO mediates vasodilation and furthermore inhibits platelet aggregation, expression of adhesion molecules for monocytes and adhesion of neutrophils, and it impairs growth of vascular smooth muscle cells. Risk factors for coronary atherosclerosis, such as hypercholesterolaemia, impair NO bioactivity, mainly due to an oxidative stress by superoxide radicals (O2-), which are able of rapidly inactivating endothelium-derived NO. Impaired NO bioactivity leads to unopposed paradoxical vasoconstriction of epicardial conductance vessels in response to physiological stimuli such as sympathetic activation as well as impaired vasodilator function of coronary resistance vessels. Therefore, endothelial dysfunction contributes to ischaemic manifestation of coronary artery disease. In addition, enhanced paradoxical vasoconstriction and a loss of endothelial antithrombotic activities might unfavourably modulate the course of acute coronary syndromes. Thus, the aim of therapeutic interventions is to increase NO bioavailability by either increasing NO production or decreasing O2- production in the endothelium. This goal can be reached, for example by ACE inhibitors, lipid-lowering drugs, increased shear-stress by physical exercise, oestrogens, and L-arginine, which have already been shown to improve endothelial vasodilator function. Nevertheless, it has to be determined whether ameliorated endothelial function will contribute to improved patients prognosis.     

Oxidative stress and hyperuricaemia: pathophysiology,clinical relevance,and therapeutic implications in chronic heart failure

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant‐producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up‐regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up‐to‐date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.     

Oxidative stress and apoptosis in heart dysfunction

BACKGROUND: Heart disease is a major cause of morbidity and mortality due to its complex pathogenesis. Myocyte cell loss through apoptosis has been reported in a variety of cardiovascular disease conditions including myocardial infarction (MI), ischemia-reperfusion injury, end-stage heart failure and adriamycin cardiomyopathy. POTENTIAL APOPTOTIC FACTORS AND THERAPEUTIC TARGET: The cell biology of the apoptotic regulatory processes and the precise role of apoptosis in the development of cardiac dysfunction need to be established. The upregulation of proapoptic proteins, like Bax (a member of the Bcl-2 family proteins), caspases and cytochrome c, with or without the downregulation of antiapoptic proteins, including Bcl-2 (another member of the Bcl family), Akt and inhibitory apoptotic proteins (IAPs), has been documented in different cardiac disease conditions. However, mitogen-activated protein kinases (MAPKs) have been shown to be involved in both apoptosis and cell survival. Apoptosis can be blocked by inhibiting apoptotic regulatory pathways with caspase inhibitors and overexpression of Bcl-2 and Akt. More recently, increased oxidative stress has been shown to promote apoptosis, and antioxidants have been shown to inhibit this process. CONCLUSION: The ability of antioxidants to inhibit these apoptotic pathways has raised the possibility of newer therapeutic treatment for various heart diseases.     

The clinical implications of endothelial dysfunction

Defining new approaches for the prevention and treatment of atherosclerosis is an important priority. Recently, measurement of endothelial function in patients has emerged as a useful tool for atherosclerosis research. Risk factors are associated with impaired endothelial function, and clinical syndromes relate, in part, to a loss of endothelial control of vascular homeostasis. Recent studies have shown that the severity of endothelial dysfunction relates to cardiovascular risk. A growing number of interventions known to reduce cardiovascular risk have been shown to improve endothelial function. This work suggests that studies of endothelial function could be used in the care of patients and as a surrogate marker for the evaluation of new therapeutic strategies. This article will review this growing literature in an effort to evaluate the current clinical utility of endothelial dysfunction.     

Oxidative stress could precede endothelial dysfunction and insulin resistance in Indian Mauritians with impaired glucose metabolism

Aims/hypothesis. To measure oxidative stress, endothelial dysfunction and insulin resistance in Indian Mauritians at different stages of development of Type II (non-insulin-dependent) diabetes mellitus. Methods. Plasma total 8-epi-PGF₂α, an indicator of oxidative stress, was determined in age-matched subjects with normal glucose metabolism (n = 39), impaired glucose tolerance (n = 14), newly diagnosed diabetes (n = 8) and established diabetes (n = 14). Plasma glucose and insulin were measured at baseline and 2 h following an oral glucose tolerance test. Endothelial function was assessed by non-invasive digital pulse wave photoplethysmography. Results. Plasma 8-epi-PGF₂α increased in subjects with impaired glucose tolerance (p < 0.05) compared with control subjects, and was even higher in newly diagnosed diabetic patients (p < 0.01) and established (p < 0.01) diabetic patients. A tendency towards reduced endothelial function in subjects with impaired glucose tolerance became significant in patients with newly diagnosed and established diabetes (p < 0.01), and was correlated with 8-epi-PGF₂α (r = 0.36, p < 0.01). Insulin resistance (homeostasis model assessment) did not change in subjects with impaired glucose tolerance compared with control subjects, but increased in newly diagnosed (p < 0.01) and established (p < 0.001) diabetic subjects. The 8-epi-PGF₂α was correlated with fasting glucose (r = 0.50, p < 0.001), triglycerides (r = 0.40, p < 0.001) and insulin resistance (r = 0.35, p < 0.001). Conclusion/interpretation. Oxidant stress is an early event in the evolution of Type II diabetes and could precede the development of endothelial dysfunction and insulin resistance. [Diabetologia (2001) 44: 706–712 Received: 1 November 2001 and in revised form: 14 February 2001     

Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia

The pregnancy disorder preeclampsia continues as a major cause of maternal and infant mortality and morbidity. Despite intensive research since its recognition 100 years ago, our lack of understanding is evidenced by therapy which remains empiric, early delivery. Part of our failure to more completely understand the syndrome is due to excessive attention to the blood pressure elevation which accompanies the disorder, to the exclusion of a panoply of other physiologic aberrations. Although hypertension, if markedly elevated, can lead to maternal morbidity, it is not usually an important contributor to the pathophysiology of preeclampsia. It is primarily important as a marker for vasoconstriction, which in association with activation of coagulation reduces perfusion to many organs, including the fetal-placental unit. The earliest and likely most important pathophysiologic change is reduced placental perfusion secondary to abnormal implantation and/or a relative increase in placental mass. We propose that reduced placental perfusion results in the production of agent(s) by this organ, which injures or activates endothelial cells. The resulting endothelial cell dysfunction increases sensitivity to normal endogenous pressors, activates the coagulation cascade, and increases vascular permeability. These changes produce the characteristic pathophysiologic changes of the disorder. Evidence supporting this hypothesis includes abnormal endothelial morphology long recognized in glomerular capillaries, increased circulating fibronectin, and increased plasma mitogenic activity that long antedates the clinical disorder. In addition, an agent(s) is present in the blood of these women which activates endothelial cells in vitro as evidenced by increased release of [51Cr] chromium and increased production of PDGF. Preeclampsia is clearly more than "pregnancy induced hypertension."     

Oxidative stress: A cause and therapeutic target of diabetic complications

Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the presence of diminished anti‐oxidant substances. Increased oxidative stress could be one of the common pathogenic factors of diabetic complications. However, the mechanisms by which hyperglycemia increases oxidative stress are not fully understood. In this review, we focus on the impact of mitochondrial derived ROS (mtROS) on diabetic complications and suggest potential therapeutic approaches to suppress mtROS. It has been shown that hyperglycemia increases ROS production from mitochondrial electron transport chain and normalizing mitochondrial ROS ameliorates major pathways of hyperglycemic damage, such as activation of polyol pathway, activation of PKC and accumulation of advanced glycation end‐products (AGE). Additionally, in subjects with type 2 diabetes, we found a positive correlation between HbA1c and urinary excretion of 8‐hydroxydeoxyguanosine (8‐OHdG), which reflects mitochondrial oxidative damage, and further reported that 8‐OHdG was elevated in subjects with diabetic micro‐ and macro‐ vascular complications. We recently created vascular endothelial cell‐specific manganese superoxide dismutase (MnSOD) transgenic mice, and clarified that overexpression of MnSOD in endothelium could prevent diabetic retinopathy in vivo. Furthermore, we found that metformin and pioglitazone, both of which have the ability to reduce diabetic vascular complications, could ameliorate hyperglycemia‐induced mtROS production by the induction of PPARγ coactivator‐1α (PGC‐1α) and MnSOD and/or activation of adenosine monophosphate (AMP)‐activated protein kinase (AMPK). We also found that metformin and pioglitazone promote mitochondrial biogenesis through the same AMPK–PGC‐1α pathway. Taking these results, mtROS could be the key initiator of and a therapeutic target for diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00013.x, 2010)