New concept of vascular calcification and metabolism

Vascular calcification is recently considered as one of the major complications and an independent risk factor of cardiovascular diseases. Although vascular calcification was commonly regarded as a passive process of mineral adsorption or precipitation, it tends to be an active process associated with the expression of growth factors, matrix proteins, and other bone-related proteins. There are 2 main types of vascular calcification. Intimal calcification is found in atherosclerotic plaques and is associated with the vascular events such as myocardial infarction. Medial calcification is usually associated with age and chronic kidney disease patients, which leads to increased vascular stiffness and reduced vascular compliance. Interestingly, our vascular calcification model using ApoE deficient mice showed intima calcification at sites of atherosclerotic plaques under high fat diet with ovariectomy. Thus, lipid metabolism is one of the therapeutic targets to prevent intima calcification of aorta. Previously we reported that ezetimibe significantly prevented atherosclerosis through lipid-lowering effects in ApoE-deficient mice. Based on these findings, we speculate that ezetimibe might prevent aortic intima calcification, which may give us the benefits to decrease vascular events.     

Targeting therapy using a monoclonal antibody against tumor vascular endothelium

Recent studies have revealed that the targeting therapy using monoclonal antibody against tumor associated antigens did not have a clinically satisfactory effect due to various physiological characters of tumor. We propose a novel approach targeting tumor vascular endothelium to solve the inefficiency of common tumor missile therapy. In this study, the tissue distribution of anti-tumor vascular endothelium monoclonal antibody (TES-23) produced by immunizing with plasma membrane vesicles obtained from isolated rat tumor-derived endothelial cells (TECs) was assessed in various tumor-bearing animals. Radiolabeled TES-23 dramatically accumulated in KMT-17 fibrosarcoma, a source of isolated TECs after intravenous injection. In Meth-A fibrosarcoma, Colon-26 adenocarcinoma in BALB/c mice and HT-1080 human tumor tissue in nude mice, radioactivities of 125I-TES-23 were also up to fifty times higher than those of control antibody with little distribution to normal tissues. Furthermore, immunostaining of human tissue sections showed specific binding of TES-23 on endothelium in esophagus and colon cancers. These results indicate that tumor vascular endothelial cells express a common antigen in different tumor types of various animal species. In order to clarify the efficacy of TES-23 as a drug carrier, an immunoconjugate, composed of TES-23 and neocarzinostatin, was tested for its antitumor effect in vivo. The immunoconjugate (TES-23-NCS) caused a marked regression of the tumor, KMT-17 in rats and Meth-A in mice. Thus, from a clinical view, TES-23 would be a novel drug carrier because of its high specificity to tumor vascular endothelium and its application to many types of cancer.     

Targeting vascular disease in systemic sclerosis

Systemic sclerosis (scleroderma, SSc) is a chronic connective tissue disease of unknown etiology characterized by progressive fibrosis of the skin and a distinctive pattern of internal organ involvement. Excessive fibrosis, vascular injury, autoimmunity and inflammation are permanent features of the disease process leading to irreversible organ damage and significant morbidity and mortality in SSc patients. Recent progress in understanding the pathogenesis of SSc as well as diagnostic and therapeutic advances in medicine have made more effective treatment strategies possible. So far, therapies targeting vascular aspects of SSc have been most successful. This underlines the role of vascular injury in the pathogenesis of the disease and raising hopes of significant improvement in the management of SSc patients. The aim of this review is to summarize recent and potential future treatments of SSc-associated vascular disease.     

Targeting NADPH oxidases in vascular pharmacology

Oxidative stress is a molecular dysregulation in reactive oxygen species (ROS) metabolism, which plays a key role in the pathogenesis of atherosclerosis, vascular inflammation and endothelial dysfunction. It is characterized by a loss of nitric oxide (NO) bioavailability. Large clinical trials such as HOPE and HPS have not shown a clinical benefit of antioxidant vitamin C or vitamin E treatment, putting into question the role of oxidative stress in cardiovascular disease. A change in the understanding of the molecular nature of oxidative stress has been driven by the results of these trials. Oxidative stress is no longer perceived as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production. NADPH oxidases are at the center of these events, underlying the dysfunction of other oxidases including eNOS uncoupling, xanthine oxidase and mitochondrial dysfunction. Thus NADPH oxidases are important therapeutic targets. Indeed, HMG-CoA reductase inhibitors (statins) as well as drugs interfering with the renin-angiotensin-aldosterone system inhibit NADPH oxidase activation and expression. Angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor antagonists (sartans) and aliskiren, as well as spironolactone or eplerenone, have been discussed. Molecular aspects of NADPH oxidase regulation must be considered, while thinking about novel pharmacological targeting of this family of enzymes consisting of several homologs Nox1, Nox2, Nox3, Nox4 and Nox5 in humans. In order to properly design trials of antioxidant therapies, we must develop reliable techniques for the assessment of local and systemic oxidative stress. Classical antioxidants could be combined with novel oxidase inhibitors. In this review, we discuss NADPH oxidase inhibitors such as VAS2870, VAS3947, GK-136901, S17834 or plumbagin. Therefore, our efforts must focus on generating small molecular weight inhibitors of NADPH oxidases, allowing the selective inhibition of dysfunctional NADPH oxidase homologs. This appears to be the most reasonable approach, potentially much more efficient than non-selective scavenging of all ROS by the administration of antioxidants.     

Targeting vascular endothelial growth factor: a promising strategy for treating age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the industrialised world. While treatment options for advanced AMD have been rather limited until recently, the introduction of intravitreal injections of anti-angiogenic agents appears to be a promising and revolutionary mode of treatment for this blinding disease. Vascular endothelial growth factor (VEGF) appears to play a pivotal role in the pathogenesis of choroidal neovascularisation, one of the cornerstones of advanced AMD. Pegaptanib, the first anti-VEGF treatment approved for AMD patients, is a VEGF-neutralising aptamer that specifically inhibits one isoform of VEGF (VEGF-165). Although evidence suggested that pegaptanib was superior to previous treatment options, results with this agent were still unsatisfactory. Ranibizumab is a humanised anti-VEGF monoclonal antibody fragment that inhibits all isotypes of VEGF. This new drug has demonstrated a high efficacy profile in terms of inhibiting disease progression and even improving visual acuity. Bevacizumab is a full-length anti-VEGF antibody that was originally approved for use in metastatic colon cancer and is under investigation as a low-cost off-label alternative for patients with AMD. There is growing evidence that this drug may be an effective and safe alternative to the more expensive ranibizumab, although prospective multicentre trials are required to fully investigate this issue. Undoubtedly, the concept of directly injecting anti-VEGF drugs into the vitreal cavity brings new hope to many AMD patients.     

Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target

Introduction: Fibroblast growth factor 19 (FGF19) is a member of the hormone-like FGF family and has activity as an ileum-derived postprandial hormone. It shares high binding affinity with β-Klotho and together with the FGF receptor (FGFR) 4, is predominantly targeted to the liver. The main function of FGF19 in metabolism is the negative control of bile acid synthesis, promotion of glycogen synthesis, lipid metabolism and protein synthesis.

Areas covered: Drawing on in vitro and in vivo studies, this review discusses FGF19 and some underlying mechanisms of action of FGF19 as an endocrine hormone in several liver diseases. The molecular pathway of the FGF19-FGFR4 axis in non-alcoholic liver disease and hepatocellular carcinoma are discussed. Furthermore, definition of function and pharmacological effects of FGF19 for liver disease are also presented.

Expert opinion: A series of studies have highlighted a crucial role of FGF19 in liver disease. However, the conclusions of these studies are partly paradoxical and controversial. An understanding of the underlying biological mechanisms which may explain inconsistent findings is especially important for consideration of potential biomarker strategies and an exploration of the putative therapeutic efficacy of FGF19 for human liver disease.     

FXR as a novel therapeutic target for vascular disease

Diseases such as atherosclerosis involve large blood vessel narrowing and hardening, an increase in activated and inflammatory cells, and an accumulation of lipids such as cholesterol. The farnesoid X receptor (FXR) is a recently identified steroid-like receptor. Bile acids are FXR ligands, which use FXR feedback to limit their own biosynthesis in the liver from cholesterol. FXR ligands have been proposed as novel targets in cardiovascular disease, as they affect lipid metabolism in the liver and gastrointestinal tract and lower circulating triglycerides and cholesterol. Recent evidence also suggests that FXR is expressed in the vasculature, implicating FXR as a novel potential 'direct' target for cardiovascular diseases. This review aims to introduce the FXR literature and discuss the mechanisms by which FXR may both directly and indirectly affect the progression of cardiovascular disease.     

Caldesmon as a therapeutic target for proliferative vascular diseases

Caldesmon is a negative regulator of cell proliferation, migration, and metalloproteinase release. Caldesmon function is regulated by multiple kinases, targeting multiple phosphorylation sites. Recently, overexpression of caldesmon has been shown to inhibit neointimal formation after experimental angioplasty, suggesting that caldesmon may be a potential therapeutic target for proliferative vascular diseases.     

Targeting vascular redox biology through antioxidant gene delivery: a historical view and current perspectives

Oxidative stress, resulting from a deregulated equilibrium between superoxide and nitric oxide (NO) production, contributes to the progression of different vascular diseases such as atherosclerosis, hypertension, ischemia/reperfusion injury and restenosis. Despite disappointing results of various oral antioxidant treatment trials, promising findings have been reported using gene delivery of enzymes to improve NO bioavailability and decrease oxidative stress in animal models for vascular diseases. NO production can be increased by overexpression of endothelial NO synthase (eNOS) in the vascular wall. However, the complex regulation of NOS needs to be carefully considered in the context of gene therapy along with the availability of its cofactor tetrahydrobiopterin and eNOS uncoupling. Furthermore, preclinical studies demonstrated that gene delivery of antioxidative vascular wall-specific enzymes, such as heme oxygenase-1, superoxide dismutase, catalase and glutathione peroxidase, has the potential to attenuate oxidative stress and inhibit atherosclerosis. Another option is to transfect vascular disease patients with secreted antioxidants such as high density lipoprotein-associated enzymes or soluble scavenger receptors. The advantage of the latter is that gene delivery of these enzymes and receptors does not need to be endothelium specific. Nonetheless, techniques to deliver genes specifically to the vascular wall are under development and hold interesting perspectives for the treatment of vascular diseases in the future. The patents relevant to gene delivery are also discussed in this review article.     

15-Lipoxygenase and its inhibition: a novel therapeutic target for vascular disease

The disease process known as atherosclerosis is the leading cause of morbidity and mortality in the Western world. Current therapies have focused on treating the major risk factors identified to date including plasma lipid derangements, hypertension, clotting disorders, and diabetes. However, a significant number of individuals will be diagnosed with this malady in the apparent absence of known risk factors. Recent attention has turned toward treating the disease at the level of the vessel wall. In this review, we assess the relevancy of the oxygenating enzyme 15-lipoxygenase (15-LO) as a therapeutic target. In vitro studies suggest that this enzyme may be involved in processes that modify native LDL in such a way as to be avidly taken up by tissue macrophages. In support of this contention are reports demonstrating the colocalization of 15-LO with macrophage-rich arterial lesions and epitopes of modified LDL. Investigations using transgenic animals also suggest that the site of 15-LO expression may be an important factor in the development of the disease. The alteration of important cellular fatty acids may also generate intracellular signals that promote a pro-atherogenic phenotype in the absence of measurable changes in bulk lipid peroxidation. A limited number of studies have examined 15-LO inhibitors and those structural determinants necessary for inhibition of the enzyme. These include natural products and synthetic analogs. Structure activity relationships have been defined for a number of compounds including caffeic acid derivatives, propargyl ethers, and catechols. A novel, potent, specific inhibitor of 15-LO that lacks significant antioxidant activity was tested for its ability to inhibit atherosclerotic lesion formation in vivo. This benzothiopyranoindole virtually eliminated lesion formation in two animal models in the absence of significant changes in plasma lipids. Further, it prevented the progression of pre-established lesions in another study. Collectively, these data provide a strong scientific rationale for exploring the inhibition of 15-LO as a therapeutic strategy.     

Targeting the cancer initiating cell: the ultimate target for cancer therapy

An area of therapeutic interest in cancer biology and treatment is targeting the cancer stem cell, more appropriately referred to as the cancer initiating cell (CIC). CICs comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts in genetically modified murine models. CICs are thought to be responsible for tumor onset, self-renewal/maintenance, mutation accumulation and metastasis. CICs may lay dormant after various cancer therapies which eliminate the more rapidly proliferating bulk cancer (BC) mass. However, CICs may remerge after therapy is discontinued as they may represent cells which were either intrinsically resistant to the original therapeutic approach or they have acquired mutations which confer resistance to the primary therapy. In experimental mouse tumor transplant models, CICs have the ability to transfer the tumor to immunocompromised mice very efficiently while the BCs are not able to do so as effectively. Often CICs display increased expression of proteins involved in drug resistance and hence they are intrinsically resistant to many chemotherapeutic approaches. Furthermore, the CICs may be in a suspended state of proliferation and not sensitive to common chemotherapeutic and radiological approaches often employed to eliminate the rapidly proliferating BCs. Promising therapeutic approaches include the targeting of certain signal transduction pathways (e.g., RAC, WNT, PI3K, PML) with small molecule inhibitors or targeting specific cell-surface molecules (e.g., CD44), with effective cytotoxic antibodies. The existence of CICs could explain the high frequency of relapse and resistance to many currently used cancer therapies. New approaches should be developed to effectively target the CIC which could vastly improve cancer therapies and outcomes. This review will discuss recent concepts of targeting CICs in certain leukemia models.     

Autophagy: an emerging therapeutic target in vascular diseases

Autophagy is a cellular catabolic process responsible for the destruction of long-lived proteins and organelles via lysosome-dependent pathway. This process is of great importance in maintaining cellular homeostasis, and deregulated autophagy has been implicated in the pathogenesis of a wide range of diseases. A growing body of evidence suggests that autophagy can be activated in vascular disorders such as atherosclerosis. Autophagy occurs under basal conditions and mediates homeostatic functions in cells but in the setting of pathological states up-regulated autophagy can exert both protective and detrimental functions. Therefore, the precise role of autophagy and its relationship with the progression of the disease need to be clarified. This review highlights recent findings regarding autophagy activity in vascular cells and its potential contribution to vascular disorders with a focus on atherogenesis. Finally, whether the manipulation of autophagy represents a new therapeutic approach to treat or prevent vascular diseases is also discussed.     

尿毒症患者血清钙化相关蛋白与血管钙化的关系研究

目的探讨尿毒症患者血清钙化相关蛋白与血管钙化的关系。方法选取尿毒症患者60例作为尿毒症组,选取严重外伤后截肢患者20例为对照组,采用von Kossa染色法观察桡动脉钙化情况;采用免疫组织化学法观察核心结合因子1(Cbfα1)、骨钙素(OC)及Toll样受体4(TLR4)的表达情况;对2组患者的组织学改变、血生化指标、血管钙化发生情况进行统计分析。结果对照组健康桡动脉无钙化;尿毒症组患者无钙化31例(52%),有钙化29例(48%),其中重度钙化11例,轻中度钙化18例,分别占总数的18%、30%;钙化血管均有Cbfα1、OC、TLR4的表达。尿毒症组患者的血磷、C反应蛋白、血清甲状旁腺激素、动脉内膜中层厚度水平均显著高于对照组(P<0.05),血管直径/桡动脉管壁显著高于对照组(P<0.05),但2组患者的血钙水平之间的差异无统计学意义(P>0.05)。结论尿毒症患者桡动脉血管钙化率高,钙化血管均有Cbfα1、OC、TLR4表达,且与血管钙化严重程度呈正相关,值得临床充分重视。     

Calcium sensitization as a pharmacological target in vascular smooth-muscle regulation

Numerous diseases have been associated with alteration(s) in smooth-muscle cell tone (ie, heightened contraction and/or diminished relaxation), including vascular disorders such as hypertension, cerebral vasospasm, coronary vasospasm and erectile dysfunction. Given the numerous steps that occur between receptor activation, signal transduction and cellular activation in vascular smooth muscle, it is not surprising that the etiology of common cardiovascular diseases/disorders is multifactorial. Nonetheless, this review will highlight the potential importance of the relationship between intracellular calcium levels and force generation, referred to as calcium sensitization, to these disease processes. As such, the complexities of the overlapping biochemical systems/pathways that govern calcium sensitization in vascular myocytes are reviewed, and the possibility that alterations in calcium sensitization may provide a common link among distinct vascular disorders is explored. A corollary of this supposition is that improved knowledge and understanding of the intrinsically complex regulation of calcium sensitization will provide novel opportunities for improved therapy of vascular disease.     

The vascular system as a target of metal toxicity.

Vascular system function involves complex interactions among the vascular endothelium, smooth muscle, the immune system, and the nervous system. The toxic metals cadmium (Cd), arsenic (As), and lead (Pb) can target the vascular system in a variety of ways, ranging from hemorrhagic injury to subtle pathogenic remodeling and metabolic changes. Acute Cd exposure results in hemorrhagic injury to the testis, although some strains of animals are resistant to this effect. A comparison of Cd-sensitive with Cd-resistant mouse strains showed that expression of the Slc39a8 gene, encoding the ZIP8 transporter, in the testis vasculature endothelium is responsible for this difference. Endogenously, ZIP8 is a Mn(2+)/HCO(3)(-)symporter that may also contribute to Cd damage in the kidney. Chronic Cd exposure is associated with various cardiovascular disorders such as hypertension and cardiomyopathy and it is reported to have both carcinogenic and anticarcinogenic activities. At noncytotoxic concentrations of 10-100nM, Cd can inhibit chemotaxis and tube formation of vascular endothelial cells. These angiostatic effects may be mediated through disruption of vascular endothelial cadherin, a Ca(2+)-dependent cell adhesion molecule. With regard to As, ingestion of water containing disease-promoting concentrations of As promotes capillarization of the liver sinusoidal endothelium. Because capillarization is a hallmark precursor for liver fibrosis and contributes to an imbalance of lipid metabolism, this As effect on hepatic endothelial cells may be a pathogenic mechanism underlying As-related vascular diseases. With regard to Pb, perinatal exposure may cause sustained elevations in adult blood pressure, and genetically susceptible animals may show enhanced sensitivity to this effect. Taken together, these data indicate that the vascular system is a critical target of metal toxicity and that actions of metals on the vascular system may play important roles in mediating the pathophysiologic effects of metals in specific target organs.     

骨质疏松症与血管钙化的相关性研究进展

骨质疏松症( OP)是以骨的微结构破坏、骨量减少、脆性增加、易发生骨折为特征的全身代谢性骨病。血管钙化( VC)是动脉粥样硬化的主要表现形式,是心血管疾病的主要病理基础。 OP与 VC的影响因素众多且复杂,该研究将从两方面讨论 OP与 VC的相关性:在临床上,老龄化、雌激素水平降低、血脂异常、高血糖、甲状旁腺激素上升、维生素 D3下降可导致 OP的同时也可促进 VC;在共同分子作用机制层面,骨保护素( OPG)、骨形态发生蛋白( BMP)、基质 Gla蛋白( MPG)、 Klotho因子( Klotho)、胎球蛋白 -A(FITUIN-A)表达抑制可导致 OP同时也可促进 VC,而 Wnt信号通路(Wnt)表达增加、骨桥蛋白( OPN)表达下降可以改善 OP但是会导致 VC。     

The polyamine pathway as a potential target for vascular diseases: focus on restenosis

Polyamines are organic polycations expressed by all living organisms, which are known to play an essential role in cell proliferation and differentiation. Recent studies revealed their involvement also in cell contractility and migration and in programmed cell death. These processes are known to contribute to restenosis, a pathophysiological process occurring in 10-20% of patients submitted to revascularization procedures. The advent of bare metal stents and of drug-eluting stents has significantly reduced but not eliminated the incidence of restenosis, which thus remains a clinically relevant problem. Despite the potential role of the polyamine pathway as a therapeutic target due to its involvement in proliferation, apoptosis and migration of vascular cells, experimental inhibition of polyamine synthesis and/or uptake has been poorly investigated in animal models of vascular disease. Here we review the current knowledge about molecular mechanisms related to polyamine functions, with particular reference to the role played by polyamines in vascular cell pathophysiology, together with experimental evidence obtained so far in animal models of (re)stenosis. We also evaluate the advantages of different routes of administration of polyamine synthesis/transport inhibitors and polyamine analogue molecules. Increasing knowledge about the molecular mechanisms and functions of polyamines is expected to shed new light on their potential role as a therapeutic target for restenosis reduction.     

Targeting vascular endothelial growth factor in angina therapy

Despite tremendous success of growth factor therapy in animal models, clinical trials have demonstrated minimal success. Vascular endothelial growth factors are perhaps the most potent inducers of angiogenesis in these animal models. This review outlines the biology of vascular endothelial growth factors in the context of myocardial angiogenesis with an emphasis on its effects on the endothelium. It also provides an overview of delivery strategies and summarises the preclinical and clinical evidence relating to exogenous growth factor delivery for myocardial angiogenesis with an emphasis on the key future challenges.     

Targeting the mammalian target of rapamycin in myxoid chondrosarcoma

Myxoid chondrosarcoma is a slow-growing sarcoma poorly responsive to chemotherapy and radiation therapy. Translational research has validated several proteins as optional therapeutic targets. Significant responses are, however, rare. In this paper we report an extraordinary response of myxoid chondrosarcoma to targeted therapy by rapamycin in combination with cyclophosphamide. Our case points to a possible novel therapeutic approach towards myxoid chondrosarcoma, by targeting the mammalian target of rapamycin protein, and probably protein kinase C-alpha, mitogen-activated protein kinase, and Jun N-terminal kinase too, by rapamycin.