The most cited articles published since 2010, extracted from Scopus
Volume 55, Issues 1-3, July 2011, Pages 10-16
Gian Paolo Aolo Fadini | Angelo Avogaro
Dipeptydil-peptidase-4 (DPP-4) inhibitors are available as oral anti-hyperglycemic drugs for the treatment of type 2 diabetes. Their metabolic effect is mediated through sparing incretin hormones (such as glucagon-like peptide-1, GLP-1) from the rapid degradation by DPP-4. In turn, GLP-1 improves meal-stimulated insulin secretion by pancreatic β-cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert beneficial effects. However, DPP-4 has several non-incretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inflammation, immunity, and vascular function. Owing to these off-target mechanisms, DPP-4 inhibitors hold promise for cardiovascular protection, but may also face unexpected side effects. Herein, we review available data on the cardiovascular effects of DPP-4 inhibitors, with a special interest in GLP-1-independent mechanisms. The modulation of endothelial progenitor cells, inflammatory pathway and ischemic response emerges as the major cardiovascular target of DPP-4 inhibitors. © 2011 Elsevier Inc.
Volume 56, Issues 5-6, January 2012, Pages 216-231
Agata Schramm | Paweł Matusik | Grzegorz Osmenda | Tomasz J. Guzik
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. © 2012 Elsevier Inc.
Volume 53, Issues 5-6, November 2010, Pages 200-208
Sylvie Lamy | Marie Paule Lachambre | Simon Lord-Dufour | Richard Béliveau
Propranolol, a non-selective β-adrenergic blocking drug, was recently reported to control the growth of hemangiomas, the most common vascular tumor of infancy. However, the mechanisms involved in this effect remain unknown. Here, we demonstrate that propranolol dose-dependently inhibited growth factor-induced proliferation of cultured human umbilical vein endothelial cells (HUVECs) through a G0/G1 phase cell cycle arrest. This was correlated to decreased cyclin D1, cyclin D3, and cyclin-dependent kinase CDK6 protein levels, while increases in the CDK inhibitors p15INK4B, p21WAF1/Cip1 and p27Kip1 were observed. Chemotactic motility and differentiation of HUVECs into capillary-like tubular structures in Matrigel were also inhibited by propranolol. Furthermore, inhibition by propranolol of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of VEGF receptor-2 lead to inhibition of downstream signaling such as the activation of the extracellular signal-regulated kinase-1/2 and the secretion of the extracellular matrix degrading enzyme MMP-2. Taken together, these results demonstrate that propranolol interferes with several essential steps of neovascularization and opens up novel therapeutic opportunities for the use of β-blockers in the treatment of angiogenesis-dependent human diseases. © 2010 Elsevier Inc.
Volume 52, Issues 3-4, March 2010, Pages 151-156
It is generally accepted that the euthyroid state is preferred for the cardiovascular system because both hyperthyroidism and hypothyroidism cause or accelerate cardiovascular diseases. And hypothyroidism is known to be associated with atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension and impaired endothelial function. In addition, recent studies suggest that hypothyroidism is associated with the emerging risk factors for atherosclerosis such as hyperhomocysteinemia and an increase in C-reactive protein level. Thyroid hormone also has direct anti-atherosclerotic effects such as blood vessel dilatation, production of vasodilatory molecules, and inhibition of angiotensin II receptor expression and its signal transduction. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modifying risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in atherogenesis and a possible application of thyroid hormone mimetics for the therapy of hypercholesterolemia and atherosclerosis. © 2009 Elsevier Inc. All rights reserved.
Volume 52, Issues 1-2, January 2010, Pages 27-36
Bonnie K. Surmi | Alyssa H. Hasty
The role of the immune system is to recognize pathogens, tumor cells or dead cells and to react with a very specific and localized response. By taking advantage of a highly sophisticated system of chemokines and chemokine receptors, leukocytes such as neutrophils, macrophages, and T-lymphocytes are targeted to the precise location of inflammation. While this is a beneficial process for acute infection and inflammation, recruitment of immune cells to sites of chronic inflammation can be detrimental. It is becoming clear that these inflammatory cells play a significant role in the initiation and progression of metabolic disorders such as atherosclerosis and insulin resistance by infiltrating the artery wall and adipose tissue (AT), respectively. Data from human studies indicate that elevated plasma levels of chemokines are correlated with these metabolic diseases. Recruitment of macrophages to the artery wall is well known to be one of the first steps in early atherosclerotic lesion formation. Likewise, recruitment of macrophages to AT is thought to contribute to insulin resistance associated with obesity. Based on this knowledge, much recent work in these areas has focused on the role of chemokines in attracting immune cells (monocytes/macrophages in particular) to these 2 sites. Thus, understanding the potential for chemokines to contribute to metabolic disease can help direct studies of chemokines as therapeutic targets. In this article, we will review current literature regarding the role of chemokines in atherosclerosis and obesity-related insulin resistance. We will focus on novel work showing that chemokine secretion from endothelial cells, platelets, and adipocytes can contribute to immune cell recruitment, with a diagram showing the time course of chemokine expression and leukocyte recruitment to AT. We will also highlight a few of the less-commonly known chemokine-chemokine receptor pairs. Finally, we will discuss the potential for chemokines as therapeutic targets for treatment of atherosclerosis and insulin resistance. © 2009 Elsevier Inc. All rights reserved.
Volume 57, Issues 2-4, September 2012, Pages 91-97
Cristiano Capurso | Antonio Capurso
With a positive caloric balance, adipocytes undergo excessive hypertrophy, which causes adipocyte dysfunction, as well as adipose tissue endocrine and immune responses. A preferential site of fat accumulation is the abdominal-perivisceral region, due to peculiar factors of the adipose tissue in such sites, namely an excess of glucocorticoid activity, which promotes the accumulation of fat; and the greater metabolic activity and sensitivity to lipolysis, due to increased number and activity of β3-adrenoceptors and, partly, to reduced activity of α2-adrenoceptors. As a consequence, more free fatty acids (FFA) are released into the portal system.Hypertrophic adipocytes begin to secrete low levels of TNF-α, which stimulate preadipocytes and endothelial cells to produce MCP-1, in turn responsible for attracting macrophages to the adipose tissue, thus developing a state of chronic low-grade inflammation which is causally linked to insulin resistance.Excess of circulating FFA, TNF-α and other factors induces insulin resistance. FFA cause insulin resistance by inhibiting insulin signaling through the activation of serin-kinases, i.e. protein kinase C-Θ, and the kinases JNK and IKK, which promote a mechanism of serine phosphorylation of Insulin Receptor Substrates (IRS), leading to interruption of the downstream insulin receptor (IR) signaling. TNF-α, secreted by hypertrophic adipocytes and adipose tissue macrophages, also inhibits IR signaling by a double mechanism of serine-phosphorylation and tyrosine-dephosphorylation of IRS-1, causing inactivation and degradation of IRS-1 and a consequent stop of IR signaling.Such mechanisms explain the transition from excess adiposity to insulin resistance, key to the further development of type 2 diabetes. © 2012 Elsevier Inc..
Volume 52, Issues 1-2, January 2010, Pages 1-10
Shobha S. Ghosh | Bin Zhao | Jinghua Bie | Jingmei Song
Accumulation of cholesteryl esters (CE) stored as cytoplasmic lipid droplets is the main characteristic of macrophage foam cells that are central to the development of atherosclerotic plaques. Since only unesterified or free cholesterol (FC) can be effluxed from the cells to extracellular cholesterol acceptors, hydrolysis of CE is the obligatory first step in CE mobilization from macrophages. This reaction, catalyzed by neutral cholesteryl ester hydrolase (CEH), is increasingly being recognized as the rate-limiting step in FC efflux. CEH, therefore, regulates the process of reverse cholesterol transport and ultimate elimination of cholesterol from the body. In this review, we summarize the earlier controversies surrounding the identity of CEH in macrophages, discuss the characteristics of the various candidates recognized to date and examine their role in mobilizing cellular CE and thus regulating atherogenesis. In addition, physiological requirements to hydrolyze lipid droplet-associated substrate and complexities of interfacial catalysis are also discussed to emphasize the importance of evaluating the biochemical characteristics of candidate enzymes that may be targeted in the future to attenuate atherosclerosis. © 2009 Elsevier Inc. All rights reserved.
Volume 53, Issues 3-4, September 2010, Pages 77-87
Rupinder K. Sodhi | Nirmal K. Singh | Amteshwar Singh Ingh Jaggi
Poly(ADP-ribose) polymerases (PARPs) are a family of cell signaling enzymes present in eukaryotes, which are involved in the poly(ADP-ribosylation) of DNA binding proteins. While an 18 member superfamily of PARPs has been identified, however PARP-1 the most abundant isoform accounts for more than 90% of its functions. PARP-1 works as DNA damage nick sensor, which uses NAD + to form polymers of ADP-ribose (PAR) and nicotinamide. Three consequences of the activation of PARP-1 are particularly important for drug development: first, its role in DNA repair; second, its capacity to deplete cellular energetic pools, which culminates in cell dysfunction and necrosis; and third, its capacity to promote the transcription of proinflammatory genes. Consequently, pharmacological inhibition of PARP has the potential to enhance the cytotoxicity of certain DNA-damaging anticancer drugs, reduce cell necrosis (for example, in stroke or myocardial infarction) and downregulate multiple simultaneous pathways of inflammation and tissue injury (for example, in circulatory shock, colitis or diabetic complications). Through this article we have tried to develop a brief and simplified picture of the principal physiological and pathophysiological roles governed by PARP-1 and its therapeutic implications. © 2010 Elsevier Inc.
Volume 55, Issues 1-3, July 2011, Pages 2-9
Zubair I. Shah | Colleen Pineda | Thomas Kampfrath | Andrei Maiseyeu | Zhekang Ying | Ira O. Racoma | Jeffrey A. Deiuliis | Xiaohua Xu | Qinghua Sun | Susan D. Moffatt-Bruce | Frederick A. Villamena | Sanjay T. Rajagopalan
Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways.Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9-39 (88±6 vs. 91±2, p<0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-N G-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser 1177 and Ser 473 respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt.DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels. © 2011 Elsevier Inc.
Volume 54, Issues 3-6, March 2011, Pages 68-74
Rosalinda Madonna | Raffaele De Caterina
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. © 2011 Elsevier Inc.
Volume 56, Issues 5-6, May 2012, Pages 232-244
Andrew C. Newby
The matrix metalloproteinases (MMPs) are 23 secreted or cell surface proteases that act together and with other protease classes to turn over the extracellular matrix, cleave cell surface proteins and alter the function of many secreted bioactive molecules. In the vasculature MMPs influence the migration proliferation and apoptosis of vascular smooth muscle, endothelial cells and inflammatory cells, thereby affecting intima formation, atherosclerosis and aneurysms, as substantiated in clinical and mouse knockout and transgenic studies. Prominent counterbalancing roles for MMPs in tissue destruction and repair emerge from these experiments. Naturally occurring tissue inhibitors of MMPs (TIMPs), pleiotropic mediators such as tetracyclines, chemically-synthesised small molecular weight MMP inhibitors (MMPis) and inhibitory antibodies have all shown effects in animal models of vascular disease but only doxycycline has been evaluated extensively in patients. A limitation of broad specificity MMPis is that they prevent both matrix degradation and tissue repair functions of different MMPs. Hence MMPis with more restricted specificity have been developed and recent studies in models of atherosclerosis accurately replicate the phenotypes of the corresponding gene knockouts. This review documents the established actions of MMPs and their inhibitors in vascular pathologies and considers the prospects for translating these findings into new treatments. © 2012 Elsevier Inc.
Volume 55, Issues 1-3, July 2011, Pages 17-25
Matthias R. Meyer | Eric R. Prossnitz | Matthias Barton
Endogenous estrogens are important regulators of cardiovascular homeostasis in premenopausal women and delay the development of hypertension and coronary artery disease. These hormones act via three different estrogen receptors affecting both gene transcription and rapid signaling pathways in a complex interplay. In addition to the classical estrogen receptors ERα and ERβ, which are known mediators of estrogen-dependent vascular effects, a G protein-coupled estrogen receptor termed GPER that is expressed in the cardiovascular system has recently been identified. Endogenous human 17β-estradiol, selective estrogen receptor modulators (SERMs) including tamoxifen and raloxifene, and selective estrogen receptor downregulators (SERDs) such as ICI 182,780 are all agonists of GPER, which has been implicated in the regulation of vasomotor tone and protection from myocardial ischemia/reperfusion injury. As a result, understanding the individual role of ERα, ERβ, and GPER in cardiovascular function has become increasingly complex. With accumulating evidence that GPER is responsible for a variety of beneficial cardiovascular effects of estrogens, this receptor may represent a novel target to develop effective strategies for the treatment of cardiovascular diseases by tissue-specific, selective activation of estrogen-dependent molecular pathways devoid of side effects seen with conventional hormone therapy. © 2011 Elsevier Inc.
Volume 57, Issue 1, August 2012, Pages 48-55
Massimiliano Gnecchi | Patrizia Danieli | Elisabetta Cervio
Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in the bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, because of their easy preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vascular cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and may greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. In this review we will focus on the current understanding of MSC biology and MSC mechanism of action in cardiac repair. © 2012 Elsevier Inc.
Volume 57, Issues 5-6, November 2012, Pages 160-167
Ravichandran Ramasamy | Shifang Yan | Ann Marie Schmidt
The multi-ligand receptor RAGE was discovered on account of its ability to bind and transduce the cell stress-provoking signals of advanced glycation endproducts (AGEs). The finding that RAGE also bound pro-inflammatory molecules set the stage for linking RAGE and inflammation to the pathogenesis of diabetic macro- and microvascular complications. In this review, we focus on the roles of RAGE and its ligands in diabetes complications. We recount the findings from mice, rats, swine and human subjects suggesting that RAGE action potently contributes to vascular, inflammatory and end-organ stress and damage in types 1 and 2 diabetes. We detail the efforts to track ligands and RAGE in human subjects with diabetes to address if this axis may be a biomarker reflective of the state of the diabetic complications. Lastly, we suggest specific strategies to tackle AGE-ligand-RAGE interactions as potential therapeutic targets for diabetes and its complications. © 2012 Elsevier Inc..
Volume 55, Issue 4, October 2011, Pages 79-86
Andrea Caporali | Costanza Emanueli
The term angiogenesis derives from the Greek words 'angeio' meaning blood vessel, and 'genesis' meaning production or birth, together referring to the creation of blood vessels within the body. This term has been used to generally indicate the growth and remodeling process of the primitive vascular network into a complex network during pre-natal development. After birth, reparative angiogenesis is activated during wound healing and in response to ischemia, while pathological angiogenesis contributes to tumor growth and metastasis, arthritis and ocular diseases, such as diabetic retinopathy.MicroRNAs (miRNAs) are a class of endogenous, small, non-coding RNAs that control gene expression by acting on target mRNAs for promoting either their degradation or translational repression. There is increasing evidence that miRNAs play important roles in vascular development as well as in vascular diseases. In this review, we aim at describing the role of miRNAs in angiogenesis, focusing, in particular, on post-ischemic neovascularization. First, we will describe the regulation and the expression of miRNAs in endothelial cells. Then, we will analyze the role of miRNAs in reparative and pathological angiogenesis. Finally, we will discuss the innovative strategies available to inhibit the level of pathogenic anti-angiogenic miRNAs and to increase expression of therapeutic miRNAs. © 2011 Elsevier Inc.
Volume 52, Issues 3-4, March 2010, Pages 142-145
Mary K. Luidens | Shaker A. Mousa | Faith B. Davis | Hungyun Lin | Paul J. Davis
In models of thyroid hormone-induced cardiac hypertrophy, there is appropriate, supportive angiogenesis. Twenty years ago in one such model, angiogenesis in response to the hormone was observed before hypertrophy developed and it is now understood that iodothyronines induce neovascularization in a variety of settings, including the heart, ischemic striated muscle and tumor beds. The molecular mechanism of the proangiogenic action of thyroid hormone is both nongenomic and genomic. It is initiated nongenomically at the cell surface receptor for the hormone on integrin αvβ3. Kinase transduction of the hormone signal and, ultimately, transcription of several anagiogenesis-relevant genes result. The genes include basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In addition, the integrin receptor for thyroid hormone (l-thyroxine, T4, and 3, 5, 3′-triiodo-l-thyronine, T3) engages in crosstalk with the VEGF and bFGF receptors. Occlusion with tetraiodothyroacetic acid (tetrac) of the hormone receptor on the integrin in the absence of T4 and T3 suppresses the angiogenic effects of VEGF and bFGF. Tetrac also blocks the proangiogenic actions of T4 and T3. Other thyroid hormone analogues that are angiogenic include diiodothyropropionic acid (DITPA) and the nuclear thyroid hormone receptor-β-selective agonist, GC-1. Thyroid hormone sustains angiogenesis and coronary blood flow about infarcted heart tissue in experimental models and blocks deleterious heart remodeling that otherwise is predictable in such tissue. The hormone may also induce expression of the hypoxia-inducible factor 1α (HIF1α) gene, a transcription factor important to coronary artery collateralization in the setting of hypoxia. The hormone also causes transcription of the matrix Gla protein (MGP) gene that opposes vascular smooth muscle calcification. © 2009.
Volume 58, Issues 1-2, January 2013, Pages 3-20
Andreas Leiherer | Axel Mündlein | Heinz Einz Drexel
Type 2 diabetes mellitus is an inflammatory disease and the mechanisms that underlie this disease, although still incompletely understood, take place in the adipose tissue of obese subjects. Concurrently, the prevalence of obesity caused by Western diet's excessive energy intake and the lack of exercise escalates, and is believed to be causative for the chronic inflammatory state in adipose tissue. Overnutrition itself as an overload of energy may induce the adipocytes to secrete chemokines activating and attracting immune cells to adipose tissue. But also inflammation-mediating food ingredients like saturated fatty acids are believed to directly initiate the inflammatory cascade. In addition, hypoxia in adipose tissue as a direct consequence of obesity, and its effect on gene expression in adipocytes and surrounding cells in fat tissue of obese subjects appears to play a central role in this inflammatory response too.In contrast, revisiting diet all over the world, there are also some natural food products and beverages which are associated with curative effects on human health. Several natural compounds known as spices such as curcumin, capsaicin, and gingerol, or secondary plant metabolites catechin, resveratrol, genistein, and quercetin have been reported to provide an improved health status to their consumers, especially with regard to diabetes, and therefore have been investigated for their anti-inflammatory effect. In this review, we will give an overview about these phytochemicals and their role to interfere with inflammatory cascades in adipose tissue and their potential for fighting against inflammatory diseases like diabetes as investigated in vivo. © 2012 Elsevier Inc.
Volume 54, Issues 3-6, March 2011, Pages 59-67
Elle C. Flood | Katherine A. Hajjar
Optimal fibrin balance requires precisely controlled plasmin generation on the surface of endothelial cells, which line the blood vessel wall. As a co-receptor for plasminogen and tissue plasminogen activator (tPA), which are key factors in plasmin generation, the annexin A2 (A2) complex promotes vascular fibrinolysis. The intracellular A2 complex is a heterotetramer of two A2 monomers and two copies of the associated protein, p11. In response to endothelial cell activation, A2 is phosphorylated by src-kinase, and translocated to the cell surface in a highly regulated manner. Over-expression of A2 is seen in acute promyelocytic leukemia during the early hemorrhagic phase, while high titer antibodies to A2, as in antiphospholipid syndrome or cerebral venous thrombosis, are associated with thrombosis. In experimental hyperhomocysteinemia, moreover, derivatization of A2 by homocysteine leads to intravascular fibrin accumulation and dysangiogenesis, features that phenocopy the Anxa2-/- mouse. Exogenous A2 may also offer a novel therapeutic approach to ischemic thrombotic stroke, as administration of A2 in conjunction with conventional tPA-based thrombolytic therapy improved outcome in an animal model. Here, we discuss the role of the A2 system in vascular homeostasis, the molecular interactions that regulate its profibrinolytic activity, and its potential role in the pathogenesis and treatment of vascular disease. © 2011 Elsevier Inc.
Volume 53, Issues 3-4, September 2010, Pages 94-98
Waisan Cheang | Wingtak Wong | Bing Shen | Chiwai Lau | Xiaoyu Tian | Sukying Tsang | Xiaoqiang Yao | Zhenyu Chen | Yu Huang
The present study aimed at examining the role of potassium channels and endothelium in relaxations induced by sodium hydrogen sulphide (NaHS), which is the donor of gaseous hydrogen sulphide (H2S) and the effect of NaHS on endothelium-dependent relaxations in rat coronary arteries. Rat coronary arteries were suspended in a myograph for force measurement and changes of the membrane potential in arteries were determined by membrane potential-sensitive fluorescence dye. NaHS relaxed coronary arteries pre-contracted by U46619 and the relaxation was significantly less in high KCl-contracted rings. NaHS-induced relaxations were reduced by 4-aminopyridine (4-AP) but unaffected by glibenclamide, iberiotoxin, NG-nitro-L-arginine methyl ester, ODQ, indomethacin or by endothelium removal. The inhibitory effect of 4-AP was absent in NaHS-induced relaxations in high KCl-contracted rings. Addition of NaHS caused membrane hyperpolarization and this effect was inhibited by 4-AP but not by glibenclamide. NaHS causes endothelium-independent relaxations in rat coronary arteries partially through activation of 4-AP-sensitive potassium channel and ensuring hyperpolarization. Other potassium channels, Na+-K+ pump or endothelium-derived relaxing factors play little role. © 2010 Elsevier Inc.
Volume 57, Issues 5-6, November 2012, Pages 168-172
Nathan D. Roe | Jun Ren
Nitric oxide synthase enzyme (NOS) possesses the unique ability to be "uncoupled" to produce superoxide anion (O2 -) instead of nitric oxide (NO). Reduced NO bioavailability as a result of NOS uncoupling has been speculated to play an essential role in cardiovascular pathologies including dilated cardiomyopathy, ischemia reperfusion injury, endothelial dysfunction, atherosclerosis, hypertension and diabetes mellitus. NO serves many important roles in the heart including stimulation of adenylate cyclase (AC) at low levels or guanalyl cyclase (sGC) at higher levels, or by s-nitrosylation of intracellular Ca2+ regulatory proteins thus altering excitation-contraction coupling. Not surprisingly, NOS uncoupling is an emerging therapeutic target in cardiovascular diseases. Restoring proper NOS activity by increasing intracellular levels of its cofactor tetrahydrobiopterin (BH4) is effective in the management of hypertensive diastolic dysfunction, ischemia-reperfusion injury, myocardial infarction and endothelial dysfunction. New evidence is constantly emerging highlighting the importance of NOS uncoupling in cardiovascular pathologies thus the purpose of this mini-review is to showcase the new advances and promising treatments for NOS uncoupling in CV disease. © 2012 Elsevier Inc.
Volume 55, Issue 4, October 2011, Pages 111-118
Valeria Di Stefano | Germana Zaccagnini | Maurizio C. Capogrossi | Fabio Martelli
A host of studies have established essential roles for microRNAs in cardiovascular development and disease. Moreover, the discovery of stable microRNAs in bodily fluids indicated their potential as non-invasive biomarkers. In this review, we summarize the current studies describing microRNAs in blood cells or serum/plasma, as potential biomarkers of cardiovascular disease. © 2011 Elsevier Inc.
Volume 53, Issues 5-6, November 2010, Pages 273-280
Kowoon Choi | Hyejin Park | Da Hye Jung | Tae-Wan Kim | YoonMoon Park | Byungoh Kim | Eunhwa Sohn | Eunyi Moon | Sunghee Um | Dongkwon Rhee | Suhkneung Pyo
Atherosclerosis is a chronic inflammatory disease and the expression of adhesion molecules on vascular smooth muscle cells (VSMCs) contributes to the progress of the disease. Diosgenin, a precursor of steroid hormones, has been shown to have a variety of biological activities including anti-inflammatory activity; however, its molecular mechanisms are poorly understood. This study examined the effect of diosgenin on the expression of adhesion molecules induced by TNF-α in cultured mouse VSMC cell line, MOVAS-1. Preincubation of VSMCs for 2. h with diosgenin (0.1-10 μM) dose-dependently inhibited TNF-α-induced adhesion of THP-1 monocytic cells and mRNA and protein expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Diosgenin abrogated TNF-α induced production of intracellular reactive oxygen species (ROS) and phosphorylation of p38, ERK, JNK and Akt. Diosgenin was also shown to inhibit NK-κB activation induced by TNF-α. Furthermore, diosgenin inhibited TNF-α-induced IκB kinase activation, subsequent degradation of IκBκ, and nuclear translocation of NF-κB. Our results indicate that diosgenin inhibits the adhesive capacity of VSMC and the TNF-α-mediated induction of ICAM-1 and VCAM-1 in VSMC by inhibiting the MAPK/Akt/NF-κB signaling pathway and ROS production, which may explain the ability of diosgenin to suppress inflammation within the atherosclerotic lesion and modulate immune response. © 2010.
Volume 57, Issues 5-6, November 2012, Pages 139-149
Stephen W. Schäffer | Chianju Jong | Mahmood S. Mozaffari
Oxidative stress is recognized as a key participant in the development of diabetic complications in the vasculature. One of the seminal studies advancing the role of oxidative stress in vascular endothelial cells proposed that oxidative stress-mediated diversion of glycolytic intermediates into pathological pathways was a key underlying element in the development of diabetic complications. It is widely recognized that flux through glycolysis slows during diabetes. However, several bottlenecks develop in the glycolytic pathway, including glucose transport, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase. Of these limiting steps in glycolysis, glyceraldehyde-3-phosphate dehydrogenase is most sensitive to oxidative stress, leading to the hypothesis that glyceraldehyde-3-phosphate inactivation by ribosylation underlies the diversion of glycolytic intermediates into pathological pathways. However, recent studies question the mechanism underlying the effect of reactive oxygen species on key enzymes of the glycolytic pathway. The present review critiques the major premises of the hypothesis and concludes that further study of the role of oxidative stress in the development of diabetes-mediated vasculature dysfunction is warranted. © 2012 Elsevier Inc..
Volume 57, Issues 5-6, November 2012, Pages 133-138
Large randomized studies have established that early intensive glycemic control reduces the risk of diabetic complications, both micro and macrovascular. However, epidemiological and prospective data support a long-term influence of early metabolic control on clinical outcomes. This phenomenon has recently been defined as "metabolic memory." Potential mechanisms for propagating this "memory" may be the production of reactive species unrelated to the presence of hyperglycemia, depending on the previous production of AGEs which can maintain RAGE over-expression, on the level of glycation of mitochondrial proteins and on the amount of mtDNA produced, all conditions able to induce an altered gene expression which may be persistent even when glycemia is normalized. Clinically, the emergence of this "metabolic memory" suggests the need for a very early aggressive treatment aiming to "normalize" the metabolic control and the addition of agents which reduce cellular reactive species and glycation in addition to normalizing glucose levels in diabetic patients in order to minimize long-term diabetic complications. © 2012 Elsevier Inc.
Volume 55, Issue 4, October 2011, Pages 92-105
Dorothee Hartmann | Thomas Thum
MicroRNAs (miRNAs) are small non-coding RNAs, that control diverse cellular functions by either promoting degradation or inhibition of target messenger RNA translation. An aberrant expression profile of miRNAs has been linked to human diseases, including cardiovascular dysfunction. This review summarizes the latest insights in the identification of vascular-specific miRNAs and their targets, as well as their roles and mechanisms in the vasculature. Furthermore, we discuss how manipulation of these miRNAs could represent a novel therapeutic approach in the treatment of vascular dysfunction. © 2011 Elsevier Inc.