Nrf2及其药理性活化剂在糖尿病心血管并发症中的作用

糖尿病(DM)导致的心脑血管并发症是危害人类健康的重大疾病。氧化应激被认为是DM相关心血管并发症发生、发展的重要机制,但通过补充外源性抗氧化剂并未能使心血管疾病患者远期获益。核因子E2相关因子2(Nrf2)可增加内源性抗氧化酶的活性从而提高机体的抗氧化应激能力,可能是治疗糖尿病心血管并发症的一个重要靶点,提示靶向Nrf2药物的开发可能获得防治糖尿病相关血管并发症的新一代药物。本文就Nrf2在糖尿病相关心血管并发症发生、发展中的作用及其药理性活化剂对糖尿病(DM)相关心血管病变的治疗作用进行综述。     

2 型糖尿病治疗药物研究进展

2 型糖尿病（T2DM）是一种代谢障碍性疾病。传统抗糖尿病药物具有不同程度的副作用,如低血糖、胃肠道反应、体重增加、 心血管风险等,因此开发作用于新靶点和新作用机制的T2DM 治疗新药成为当前研究的热点。目前基于新靶点设计的糖尿病治疗新药有 些已上市,且获得良好的降糖效果,但大部分药物仍处于临床或临床前研究阶段,其疗效和安全性有待进一步临床验证。综述传统抗糖 尿病药物、T2DM 药物新靶点及基于新靶点设计的抗糖尿病新药的研究进展。     

2型糖尿病血管内皮损伤与内质网应激

本文对内质网应激与2型糖尿病血管内皮损伤的关系进行综述。糖尿病已成为21世纪世界范围内的一种流行病,内质网应激不仅参与了糖尿病的发病机制,同时也在其心血管并发症的发生中起着重要作用。研究发现血管内皮的损伤是其并发症的基本机制。高血糖能引发内质网应激直接造成内皮损伤,而内质网应又可激通过炎症反应间接损伤内皮,所以保护内质网功能成为了一种可能的治疗方案。     

自噬:心血管疾病治疗的新靶点

心血管疾病严重危害人类健康,是全球首要死亡原因。研究发现自噬与心血管疾病的发生、发展密切相关,并且在心肌细胞、心脏成纤维细胞、内皮细胞、血管平滑肌细胞以及巨噬细胞中得到广泛研究。细胞自噬在维持心血管系统稳态及功能方面至关重要,过度或不足的自噬流则可导致心血管系统疾病。本文不仅论述自噬在心血管细胞和疾病中的调控机制及作用,还探讨了自噬作为心血管疾病潜在的治疗靶点,为今后心血管疾病的研究和防护开拓了新的思路。     

阿片肽与P2Y12受体信号通路的研究进展

糖尿病可增加心血管疾病危险性,因此糖尿病和心血管疾病的密切关系也日益被人们所重视。糖尿病引发的血小板功能亢进以及抗血小板药物抵抗的机制尚不明确。阿片肽类物质能够抑制血小板细胞活性以及凝集作用。本文对2型糖尿病血小板P2Y12信号通路高反应性、阿片肽及阿片受体对抗P2Y12信号通路高反应性的可能机制进行了归纳总结。     

阿片肽与P2Y12 受体信号通路的研究进展

糖尿病可增加心血管疾病危险性,因此糖尿病和心血管疾病的密切关系也日益被人们所重视。糖尿病引发的血小板功能亢进以及抗血小板药物抵抗的机制尚不明确。阿片肽类物质能够抑制血小板细胞活性以及凝集作用,本文对2型糖尿病血小板P2Y12信号通路高反应性、阿片肽及阿片受体对抗P2Y12信号通路高反应性的可能机制进行了归纳总结。     

MicroRNA在靶向治疗缺血性心脏病中的研究进展

MicroRNA（MiRNA,miR）通过调节信使RNA（mRNA）的表达,广泛参与心血管系统细胞的增殖、迁移、分化、凋亡等病理生理过程,在心血管系统疾病的发生发展过程中起着重要的调控作用。越来越多的研究表明,针对缺血性心血管疾病的发病机制,通过特异性调节miRNA的活性,抑制相关蛋白的表达,对各种缺血性心脏病具有显著的治疗作用。但目前开发miRNA靶向治疗药物尚缺乏大规模的临床试验研究,其有效性和安全性需进一步证实。本文旨在综述MicroRNA在靶向治疗缺血性心脏病中的研究进展,以期为开发MiRNA靶向治疗药物治疗缺血性心脏病提供更多的理论依据。     

TXA2/PGI2与心血管疾病

血栓素(Thromboxane,TXA2)和前列环素(Prostacyclin,PGI2)均为花生四烯酸的代谢物,是前列腺素(Prostaglandins,PGs)中生物活性最强的一对。在正常情况下,二者在体内保持一定的平衡,相互拮抗、相互协调,共同维持血液循环畅通,与心血管疾病关系密切。本文即就其生物特性及与心血管病的关系等进行综述,对人们全面认识TXA2/PGI2具有一定的参考价值。     

Lp(a)在糖尿病血管并发症中的表达与机制

2型糖尿病患病率逐年上升,糖尿病血管病变是主要的慢性并发症之一,是糖尿病致死率、致残率居高不下的重要原因。脂蛋白a[lipoprotein(a),Lp(a)]是2型糖尿病及血管并发症的有效预测因子与危险因素,通过促进动脉粥样硬化、促进血栓形成、抗血管生成、诱导炎症和氧化应激等机制参与胰岛素抵抗和脂代谢异常的进程,Lp(a)与凝血功能、肾功能等相关指标有明显相关性,有望成为糖尿病血管并发症早期诊断和评估预后的潜在生物学标志物。该文旨在对Lp(a)在糖尿病血管并发症的表达与机制作一综述,以期提高其临床应用价值。     

花生四烯酸与动脉粥样硬化和血栓形成的关系

花生四烯酸 (AA) 对机体有类似前列腺素(PG)的广泛作用,尤其是对血液和心血管有重要的影响。AA有降低血胆固醇、舒张血管平滑肌、降低血压、增加窦房结频率和心肌收缩力、舒张冠状动脉、增加冠状动脉血流量以及抗心率不齐等作用。AA有很强的使血小板聚集的作用,主要是通过其生物合成血栓素(thromboxane A_2,TXA_2) 而起作用;而它的另一种生物合成产物前列环素 (PGI_2) 的作用恰相反。动脉粥样硬化和血栓形成,主要是由于血管壁AA生物合成PGI_2减少,而血小板生物合成TXA_2增多所致。动脉粥样硬化症与花生四烯酸代谢有一定关系,利用影响AA生物合成TXA_2和PGI_2的药物,可能对防治动脉粥样硬化和血栓形成有重要意义。     

G13 is an essential mediator of platelet activation in hemostasis and thrombosis

Platelet activation at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. Platelet activators such as adenosine diphosphate, thrombin or thromboxane A(2) (TXA(2)) activate receptors that are coupled to heterotrimeric G proteins. Activation of platelets through these receptors involves signaling through G(q), G(i) and G(z) (refs. 4-6). However, the role and relative importance of G(12) and G(13), which are activated by various platelet stimuli, are unclear. Here we show that lack of Galpha(13), but not Galpha(12), severely reduced the potency of thrombin, TXA(2) and collagen to induce platelet shape changes and aggregation in vitro. These defects were accompanied by reduced activation of RhoA and inability to form stable platelet thrombi under high shear stress ex vivo. Galpha(13) deficiency in platelets resulted in a severe defect in primary hemostasis and complete protection against arterial thrombosis in vivo. We conclude that G(13)-mediated signaling processes are required for normal hemostasis and thrombosis and may serve as a new target for antiplatelet drugs.     

Role of platelet and vascular eicosanoids in the pathophysiology of ischemic heart disease

The role of platelet and vascular arachidonate metabolism in ischemic heart disease can be derived from direct measurements and/or inhibitor trials. Direct measurements have yielded somewhat conflicting results, largely related to analytical problems and ex vivo platelet activation during blood sampling. On the other hand, inhibitor trials have clearly established the following: 1) thromboxane (TX) A2-dependent platelet activation plays an important role in the dynamic process of coronary thrombosis in unstable angina, 2) TXA2 does not appear to mediate coronary vasospasm, as seen in variant angina, 3) endogenous prostacyclin (PGI2) is not released in response to myocardial ischemia and is unlikely to regulate coronary blood flow, and 4) exogenous PGI2 is of limited therapeutic benefit. The demonstration that low-dose aspirin (0.5-1.0 mg/(kg X day] is a selective inhibitor of TXA2-dependent platelet function provides a conceptual and practical framework for the rational design of future trials. Moreover, the identification of major enzymatic metabolites of TXB2 in plasma (11-dehydro-TXB2) and urine (2,3-dinor-TXB2) and development of appropriate analytical techniques offer the opportunity for better defining the pathophysiological role of TXA2 in humans.     

Differential effects of megavitamin E on prostacyclin and thromboxane synthesis in streptozotocin-induced diabetic rats

Diabetic subjects tend to develop microvascular complications believed to be due to platelet hyperaggregability. This increased platelet sensitivity is though to be the result of an imbalance of PGI2 and TXA2 production in diabetes. This study sought to determine whether megavitamin E supplementation could restore PGI2/TXA2 balance in streptozotocin-diabetic rats. Endogenous release of PGI2 by isolated aorta, determined via radioimmunoassay of its stable metabolite, 6-keto-PGF1 alpha, was significantly greater (P less than 0.05) in rats receiving 100x the normal vitamin E requirement than in untreated diabetic rats. PGI2 synthesis was negatively correlated with plasma glucose levels (r = -0.87, P less than 0.05) in non-fasted rats at sacrifice. Vitamin E supplementation, at both the 10x and the 100x level, significantly depressed (P less than 0.05) thrombin-stimulated synthesis of TXA2 in washed platelet. PGI2 and TXA2 production were expressed as a ratio. Megavitamin E therapy appears to increase this ratio over that seen in the diabetic animal. The data suggest that vitamin E, at high levels, exerts an ameliorating influence of the PGI2/TXA2 imbalance of diabetes.     

Terutroban and endothelial TP receptors in atherogenesis

Treatment of thrombotic diseases implicates the use of anti-platelet agents, anti-coagulants and pro-fibrinolytic substances. Amongst the anti-platelet drugs, aspirin occupies a unique position. As soon as it became evident that the major action of aspirin is indirect blockade, through inhibition of cyclooxygenase (COX), of the production of thromboxane A2 (TXA2), a powerful vasoconstrictor and platelet activator, research for new anti-thrombotics that interact more specifically with the production and/or the action of TXA2 was started. Terutroban (S 18886) is a selective antagonist of TP receptors, the receptors for TXA2, that are present on platelets and on vascular smooth muscle cells, but also on endothelial cells. The role played by the platelet and smooth muscle cell TP receptors in thrombotic disease is well known, and preclinical and clinical studies with terutroban have illustrated the powerful antithrombotic effects of this agent. The implication of endothelial TP receptors in the development of atherosclerotic disease has only been examined during the past five years and studies with terutroban have been crucial for understanding the role of these endothelial receptors in cardiovascular physiopathology. The goal of the present review is to discuss the arguments in favour of the hypothesis suggesting that activation of endothelial TP receptors, by causing expression of adhesion molecules, favours adhesion and infiltration of monocytes/macrophages in the arterial wall, thereby stimulating the development of atherosclerosis. The review will also highlight the important contribution of the studies performed with terutroban in this research area. The triple activity (anti-thrombotic, anti-vasoconstrictor, anti-atherosclerotic) observed with terutroban in preclinical studies, stressed by the first results in clinical development, places terutroban as an innovative drug with a unique potential for treatment of cardiovascular disorders.     

APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice

Platelets contribute to the development of metastasis, the most common cause of mortality in cancer patients, but the precise role that anti-platelet drugs play in cancer treatment is not defined. Metastatic tumor cells can produce platelet alphaIIb beta3 activators, such as ADP and thromboxane A(2) (TXA(2)). Inhibitors of platelet beta3 integrins decrease bone metastases in mice but are associated with significant bleeding. We examined the role of a novel soluble apyrase/ADPase, APT102, and an inhibitor of TXA(2) synthesis, acetylsalicylic acid (aspirin or ASA), in mouse models of experimental bone metastases. We found that treatment with ASA and APT102 in combination (ASA + APT102), but not either drug alone, significantly decreased breast cancer and melanoma bone metastases in mice with fewer bleeding complications than observed with alphaIIb beta3 inhibition. ASA + APT102 diminished tumor cell induced platelet aggregation but did not directly alter tumor cell viability. Notably, APT102 + ASA treatment did not affect initial tumor cell distribution and similar results were observed in beta3-/- mice. These results show that treatment with ASA + APT102 decreases bone metastases without significant bleeding complications. Anti-platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases.     

Inhibition of oxidative-stress-induced platelet aggregation by androgen at physiological levels via its receptor is associated with the reduction of thromboxane A2 release from platelets

BACKGROUND: Platelets play a crucial role in the development of arterial thrombosis and other pathophysiologies leading to clinical ischemic events. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis. The purposes of our study are to assess the effect of androgen at physiological concentration via its receptor on oxidative-stress-induced platelet aggregation and to further elucidate the possible mechanism. METHODS AND RESULTS: Plasma dihydrotestosterone (DHT) was determined by ELISA using a commercially available kit. Platelet aggregometer was used to measure platelet aggregation. The contents of thromboxane B(2) (TXB(2)) were assayed with radio-immunoassay. Our results showed that addition of DHT (2 nM) significantly inhibited platelet aggregation induced by hydrogen peroxide (H(2)O(2)) (10 mM, 25 mM) in PRP diluted with Tyrode's buffer. Moreover, H(2)O(2)-induced platelet aggregation decreased in sham-operated rats. However, H(2)O(2)-induced platelet aggregation significantly increased in castrated rats. Replacement of DHT inhibited H(2)O(2)-induced platelet aggregation in castrated rats. After PRP was pretreated with flutamide, H(2)O(2)-induced platelet aggregation increased in castrated rats again. Presence of DHT (2 nM) obviously inhibited H(2)O(2)-induced thromboxane A(2) (TXA(2)) release in castrated rats. Pretreatment of DHT and flutamide increased H(2)O(2)-stimulated TXA(2) release from platelet in castrated rats again. Castration caused a significant reduction in plasma testosterone and DHT levels, whereas DHT replaced at a dose of 0.25 mg/rat restored the circulating DHT to physiological levels, without being altered by treatment with flutamide. The plasma TXB(2) increased in castrated rats as compared with that in sham-operated rats. Replacement with DHT reduced plasma TXB(2) contents in castrated rats. However, flutamide supplementation increased plasma contents of TXB(2) in castrated rats again. CONCLUSION: Androgen at physiological doses via its receptor inhibits oxidative-stress-induced platelet aggregation, which is associated with the reduction of TXA(2) release from platelets.     

Pre-activated blood platelets and a pro-thrombotic phenotype in APP23 mice modeling Alzheimer's disease

Platelet activation and thrombus formation play a critical role in primary hemostasis but also represent a pathophysiological mechanism leading to acute thrombotic vascular occlusions. Besides, platelets modulate cellular processes including inflammation, angiogenesis and neurodegeneration. On the other hand, platelet activation and thrombus formation are altered in different diseases leading to either bleeding complications or pathological thrombus formation. For many years platelets have been considered to play a role in neuroinflammatory diseases such as Alzheimer's disease (AD). AD is characterized by deposits of amyloid-β (Aβ) and strongly related to vascular diseases with platelets playing a critical role in the progression of AD because exposure of platelets to Aβ induces platelet activation, platelet Aβ release, and enhanced platelet adhesion to collagen in vitro and at the injured carotid artery in vivo. However, the molecular mechanisms and the relation between vascular pathology and amyloid-β plaque formation in the pathogenesis of AD are not fully understood. Compelling evidence is suggestive for altered platelet activity in AD patients. Thus we analyzed platelet activation and thrombus formation in aged AD transgenic mice (APP23) known to develop amyloid-β deposits in the brain parenchyma and cerebral vessels. As a result, platelets are in a pre-activated state in blood of APP23 mice and showed strongly enhanced integrin activation, degranulation and spreading kinetics on fibrinogen surfaces upon stimulation. This enhanced platelet signaling translated into almost unlimited thrombus formation on collagen under flow conditions in vitro and accelerated vessel occlusion in vivo suggesting that these mice are at high risk of arterial thrombosis leading to cerebrovascular and unexpectedly to cardiovascular complications that might be also relevant in AD patients.     

Identification of galectins as novel regulators of platelet signaling and function

Platelet activation at sites of vascular injury leads to the formation of a hemostatic plug. Activation of platelets is therefore crucial for normal hemostasis. However, uncontrolled platelet activation may also lead to the formation of occlusive thrombi that can cause ischemic events. Platelets can be activated by soluble molecules including thrombin, TXA2 , adenosine diphosphate (ADP), and serotonin or by adhesive extracellular matrix (ECM) proteins such as von Willebrand factor and collagen. In this article, we review recent advances on the role of galectins in platelet physiology. By acting in either soluble or immobilized form, these glycan-binding proteins trigger platelet activation through modulation of discrete signaling pathways. We also offer new hypotheses and some speculations about the role of platelet-galectin interactions not only in hemostasis and thrombosis but also in inflammation and related diseases such as atherosclerosis and cancer.