Endothelial-to-mesenchymal transition: A novel therapeutic target for cardiovascular diseases

Endothelial-to-mesenchymal transition (EndMT) is a complex biological process in which endothelial cells lose their specific markers and acquire a mesenchymal or myofibroblastic phenotype. Similar to epithelial-to-mesenchymal transition (EMT), EndMT can be induced by multiple stimulants such as cytokines and metabolic factors that play crucial roles in the development of the cardiovascular system. Recent studies have demonstrated that EndMT may play a significant role in the pathogenesis of cardiovascular diseases (CVDs), and may represent a novel therapeutic target for cardiovascular remodeling and fibrotic disorders. The exact molecular mechanisms involved in cardiovascular pathogenesis that occur as a result of EndMT, however, are not fully explained. In this review, we reveal the multiple intercellular mechanisms of EndMT including stimulants, signaling pathways, and seek to explore the relationship between this biological process, cardiovascular system development, and CVDs that may lead to new therapeutic strategies for the treatment of CVDs.     

Ketanserin: a novel cardiovascular drug

Ketanserin is the archetype of a new class of cardiovascular drugs, the 5HT2 (S2) serotonergic receptor antagonists. In humans, ketanserin inhibits serotonin-induced vasoconstriction and platelet activation. In addition, it reduces platelet hyperactivity, blood viscosity and total serum cholesterol. The antihypertensive effect of ketanserin is more pronounced in older people, in whom it decreases blood pressure gradually to normal levels. It lowers systemic vascular resistance resulting in a reduction of pre- and afterload. It improves vascular compliance and reduces left ventricular hypertrophy. Ketanserin improves the microcirculation of the skin, in particular capillary blood flow. Placebo-controlled studies have established that ketanserin prevents amputations in patients with atherosclerosis, enhances ulcer healing in patients with scleroderma and reduces the frequency and duration of attacks in patients with Raynaud's disease. In a placebo-controlled trial the on-treatment analysis of 3071 patients with intermittent claudication (the PACK-trial) showed a 23% reduction of severe cardiovascular events with ketanserin, suggesting that ketanserin may prevent complications of atherosclerosis. The accumulated clinical evidence indicates that serotonergic antagonism opens new perspectives in the treatment of cardiovascular disease. Current clinical research with ketanserin further explores its potential as a vascular protective agent.     

Ectopic ATP synthase in endothelial cells:a novel cardiovascular therapeutic target

ATP synthase(ATPS) produces ATP in cells and is found on the inner membrane of mitochondria or the cell plasma membrane.In this presentation, we will briefly summarize the functions of ecto-ATPS in vascular endothelial cells(ECs).Ecto -ATPS is involved in adenosine metabolism on the cell surface through its ATP generation or hydrolysis activity.The ATP/ADP generated by the enzyme on the plasma membrane can bind to P2X/P2Y receptors and activate the related signaling pathways to regulate endothelial function.The-chain of ectopic ATP synthase(ATPS) on the EC surface can recruit inflammatory cells and activate cytotoxic activity to damage ECs and induce vascular inflammation.Angiostatin and other angiogenesis inhibitors can have anti-angiogenic functions by inhibiting ecto-ATPS on ECs.Ecto-ATPS on ECs is also a receptor for apoA-Ⅰ, the acceptor of cholesterol efflux,which implies the involvement in cholesterol metabolism.The main talk will focus on our recent study about shear stress regulated membrane translocation of ATPS in ECs and the consequent interaction with T lymphocytes, which caused endothelial activation.We found that laminar flow decreased level of membrane-bound ATPS(ecto-ATPS) and depleted membrane cholesterol level in ECs.In contract,oscillatory flow increased endothelial ecto-ATPS? and membrane cholesterol levels.Incubating ECs with cholesterol or depleting cellular cholesterol could mimic the effect of oscillatory or laminar flow,respectively.Knockdown of caveolin-1 expression by siRNA prevented ATPS translocation in response to shear stress.Importantly, oscillatory flow elevated the number of T cells binding to ECs,and effect that could be blocked by anti-ATPS antibody;laminar flow significantly decreased this attachment.Furthermore,the interaction of T cells and ATPS membrane translocation was elevated in the inner curvature of the aortic arch of apoE-/- mice fed a high-fat diet. Thus,our study provided the first evidence that disturbed flow and hypercholesterolemia synergistically promote T-l     

Inhibition of myocardial apoptosis as a therapeutic target in cardiovascular disease prevention: focus on caspase inhibition

Apoptosis is a type of programmed cell death that is evident during embryonic development and normal tissue turnover. When the apoptotic activity extends beyond physiologic limits, it can determine and/or contribute to those pathologic states characterized by excessive cell loss and impairment of organ function. The clinical development of caspase inhibitors may represent a potential therapeutic strategy for influencing the onset and progression of ventricular dysfunction to terminal failure. This article focuses on the caspase cascade, a fundamental enzymatic system for apoptotic cell death. Caspases do not constitute the death signals, but are implicated in their transmission. These cytoplasmic cysteine proteases have a dual role in apoptosis. Caspases can operate as initiators, activating an endonuclease that catalyzes deoxyribonucleic acid fragmentation. Alternatively, caspases can act as effectors, participating in the total disassembly of cell structures. For example, apoptosis represents the principal form of myocyte death in the region of an acute myocardial infarction. In addition, apoptosis in the region bordering the infarct can influence the development of ischemic cardiomyopathy and ventricular dilation.     

Thymidine phosphorylase: A potential new target for treating cardiovascular disease

We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.     

Vascular endothelium: target organ of cardiovascular pathologies

The endothelium plays an essential role in regulation of vascular tone. It has vasodilator, antiaggregating, anti-thrombotic and anti-inflammatory properties. In the case of endothelial dysfunction (induced by hypercholesterolaemia, hypertension and/or diabetes), all of these properties are reversed; it becomes thrombogenic, it secretes vasoconstrictor substances promoting platelet aggregation and penetration of white blood cells into the vessel wall. This endothelial dysfunction then allows the development of the atheromatous lesion. The therapeutic approach must be based on restoration of the normal physiological properties of the endothelium.     

HDL: the 'new' target of cardiovascular medicine

Clinical, experimental and epidemiological research has shown the undeniable causal relationship between low HDL plasma concentrations and cardiovascular disease. Low HDL levels are present in about 10% of the general population and represent the most frequent form of dyslipidemia in patients with coronary disease. Reduced HDL concentrations seem to be unable to eliminate efficiently the cholesterol excess at vascular wall level, contributing to the onset of the inflammatory response that typically occurs in the pathogenesis of atherosclerosis right from its earliest stages. The results of numerous studies quite convincingly suggest that HDL is capable of exerting anti-inflammatory activity either directly or by modulating the expression of a number of acute phase proteins. Although the therapeutic options currently available for raising HDL levels still show modest efficacy, both in experimental and pre-clinical fields, genetic investigation and specifically aimed pharmacological treatment have produced more encouraging results, shedding some light on the concrete possibility of being able to treat this disease in the very near future.     

微小RNA-缺血性心脏病治疗新的靶点

当前,缺血性心脏病（IHD）是世界主要死亡原因之一。IHD是指因冠状动脉不同程度的受阻引起冠状血流和心肌耗氧需求之间不平衡而导致的心肌损害,最终形成充血性心力衰竭。心脏缺血损伤后,非缺血部位的心肌出现心肌重构,如心肌间质纤维化和心肌肥厚。心肌的重构过程可使心脏功能进一步恶化,更容易诱发心律失常。微小RNA(microRNAs,miRNAs)是一类长约22个核苷酸的非编码小分子RNA,通过与靶蛋白 mRNA 3′端非编码区的不完全互补结合,抑制靶 mRNA 转录后的表达。最近大量研究显示,miRNA 在心脏病理、生理过程中发挥着重要的调控作用,尤其与心肌梗死和梗死后心脏重构的发生、发展密切相关。本文将从miRNAs在IHD中的调控作用进行阐述,并探讨以miRNAs为靶点改善IHD患者的临床转归。     

Validation of the hexose transporter of Plasmodium falciparum as a novel drug target

Chemotherapy of malaria parasites is limited by established drug resistance and lack of novel targets. Intraerythrocytic stages of Plasmodium falciparum are wholly dependent on host glucose for energy. Glucose uptake is mediated by a parasite-encoded facilitative hexose transporter (PfHT). We report that O-3 hexose derivatives inhibit uptake of glucose and fructose by PfHT when expressed in Xenopus oocytes. Selectivity of these derivatives for PfHT is confirmed by lack of inhibition of hexose transport by the major mammalian glucose and fructose transporters (Gluts) 1 and 5. A long chain O-3 hexose derivative is the most effective inhibitor of PfHT and also kills P. falciparum when it is cultured in medium containing either glucose or fructose as a carbon source. To extend our observations to the second most important human malarial pathogen, we have cloned and expressed the Plasmodium vivax orthologue of PfHT, and demonstrate inhibition of glucose uptake by the long chain O-3 hexose derivative. Furthermore, multiplication of Plasmodium berghei in a mouse model is significantly reduced by the O-3 derivative. Our robust expression system conclusively validates PfHT as a novel drug target and is an important step in the development of novel antimalarials directed against membrane transport proteins.     

Copeptin and cardiovascular disease: A review of a novel neurohormone

Neurohormones (NHs) in the cascade of the arginine vasopressin (AVP) system have drawn particular attention in the recent years. Copeptin, the C-terminal portion of provasopressin, is a novel NH of the AVP system, and is known to be co-released with AVP from hypothalamus (neurohypophysis). As a surrogate marker of the AVP system, copeptin has gradually replaced AVP in several clinical studies largely due to its structural and methodological advantages. Copeptin has been regarded as a marker of non-specific stress response, and has also been suggested to have clinical implications in a variety of non-cardiovascular (pneumonia, sepsis, etc.) and cardiovascular conditions (heart failure and acute coronary syndromes (ACSs, etc.)). However, current data on relation of copeptin with other cardiovascular conditions ( arrhythmias, etc.) are still insufficient. The present review primarily focuses on general features of copeptin, its general clinical implications, and specifically aims to cover its potential clinical value in a variety of cardiovascular conditions.     

肺孢子菌肺炎药物治疗策略及新药靶点研究进展

肺孢子菌肺炎（Pneumocystis pneumonia,PCP）是免疫功能低下患者严重的机会性感染疾病。目前临床治疗肺孢子菌肺炎常用的一线、二线药物因副作用及特定人群耐受力差等原因而应用受限,亟需开发新药并寻找新的治疗方法以改善PCP患者的预后。本文综述了近些年PCP的药物治疗策略及新的药物靶点研究进展,包括抗真菌药物、免疫调节剂的潜在应用等,以期为PCP的临床治疗提供新的参考。     

ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素一血管紧张素系统(RAS)在哺乳动物心血管活动的调节中发挥了重要的作用.随着血管紧张素转化酶(ACE)2和血管紧张素1-7[Ang-(1-7)]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支:ACE2-Ang-(1-7)-Mas轴.其中ACE2可以水解血管紧张素Ⅰ(Ang Ⅰ)、血管紧张素Ⅱ(AngⅡ)生成Ang-(1-7).Ang-(1-7)则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖.这一新分支的发现为心血管疾病的治疗提供了新靶点.     

Regulation of apoptosis in aggressive fibroblasts

Apoptosis is a central physiological mechanism for maintaining cellular stability in tissue. Synovial fibroblasts, which play a central role in the pathogenesis of rheumatoid arthritis (RA), show a resistance to apoptosis. Several molecular mechanisms are involved in such resistance. Thus, soluble Fas can bind Fas ligands (Fas-L) and hinder Fas-L induced apoptosis in fibroblasts. SUMO-1 (a small ubiquitin-like modifier) attaches to proteins post-translationally. This appears to be significantly involved in apoptosis resistance in RA fibroblasts. SUMO-1 levels are substantially increased in synovial fibroblasts from RA patients. A change in the post-translational SUMOlation pattern could represent a new target for changing the stable activation of synovial fibroblasts in RA.