Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elastin peptides have been shown to produce many biological effects on various cell types, including an endothelium- and NO-dependent vasodilatation mediated by extracellular calcium influx and intracellular calcium elevation. Under normal concentration of extracellular glucose, the vasodilatory effect is observed in adult rats and is lost with age. Here, we have studied the consequences of extracellular glucose level changes on these effects triggered by elastin peptides (10(-4)-10(-3) mg ml(-1)), on 6- and 30-month-old rats, using the tension myography and the patch-clamp techniques. Our results show that low (0 mM) or high (33 mM) extracellular glucose concentrations abolish the extracellular calcium influx induced, under normal glucose level (11 mM), by the elastin peptides in cultured human endothelial cells. Also, low or high glucose abolish the vasodilatory action of elastin peptides observed on aorta rings from adult rats under normal glucose concentration. On the contrary, a dilation of aged rat aorta is observed in the presence of elastin peptides and high glucose, whereas such dilation is not observed when the elastin peptides are added in the presence of normal glucose concentration. In aging, a restoration by high glucose of the NO-dependent vasodilatation induced by elastin peptides could enhance the production of damaging peroxynitrite, potentially altering the structure and function of the blood vessels. These results could be of importance in the evaluation and treatment of aged patients with pathophysiological dysregulations of the circulating glucose level, such as in diabetes, age-related glucose intolerance, or low glucose levels caused by inappropriate glucose control treatments.
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PMID:The age-dependent vasodilatation and endothelial calcium influx induced by elastin peptides are modulated by extracellular glucose level. 1288 57

Long-lived structural proteins, collagen and elastin, undergo continual non-enzymatic crosslinking during aging and in diabetic individuals. This abnormal protein crosslinking is mediated by advanced glycation end products (AGEs) generated by non-enzymatic glycosylation of proteins by glucose. The AGE-derived protein crosslinking of structural proteins contributes to the complications of long-term diabetes such as nephropathy, retinopathy, and neuropathy. AGE-crosslinks have also been implicated in age-related cardiovascular diseases. Potential treatment strategies for these AGE-derived complications include prevention of AGE-formation and breaking of the existing AGE-crosslinks. The therapeutic potential of the AGE-inhibitor, pimagedine (aminoguanidine), has been extensively investigated in animal models and in Phase 3 clinical trials. This review presents the pre-clinical and clinical studies using ALT-711, a highly potent AGE-crosslink breaker that has the ability to reverse already-formed AGE-crosslinks. Oral administration of ALT-711 has resulted in a rapid improvement in the elasticity of stiffened myocardium in experimental animals. Topical administration of ALT-711 was effective in improving the skin hydration of aged rats. The therapeutic potential of crosslink breakers for cardiovascular complications and dermatological alterations associated with aging and diabetes is discussed.
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PMID:Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. 1456 12

Elevated semicarbazide-sensitive amine oxidase (SSAO) activity has been observed in several human conditions, eg, diabetes, and it has been speculated that SSAO contributes to the development of vasculopathies associated with this disease. To investigate in vivo consequences of elevated expression of SSAO in vascular tissues, we have developed a transgenic model for overexpression of human SSAO in mice. A smooth muscle-specific promoter, smooth muscle alpha-actin promoter 8 (SMP8) was used. Transgenic expression of human SSAO in tissues with a high content of smooth muscle cells was confirmed by Northern blot analysis. Enzymatic analysis of homogenates from transgenic tissues showed elevated levels of SSAO activity compared to non-transgenic littermates. Furthermore, when plasma SSAO activity was analyzed, much higher activity was detected compared to plasma from control mice, indicating that plasma SSAO may originate from smooth muscle cells. Histopathological evaluation of aorta and renal artery from transgenic mice revealed an abnormal structure of the elastin tissue. Instead of the regularly folded elastic laminae normally found in tunica media of sacrificed mice, the elastic laminae were straight and unfolded with irregularly arranged elastic fibers, forming tangled webs, between the intercalating elastic laminae. These alterations of the elastin structures suggest that overexpression of SSAO has led to a reduced elasticity of the arteries. Moreover, the mean femoral arterial pressure of the SMP8 SSAO transgenic mice was significantly lower in comparison to non-transgenic littermates. This suggests that the transgenic mice have a defect in their ability to regulate blood pressure.
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PMID:Overexpression of semicarbazide-sensitive amine oxidase in smooth muscle cells leads to an abnormal structure of the aortic elastic laminas. 1457 91

Diabetes now accounts for >40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n = 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n = 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.
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PMID:Alterations in the renal elastin-elastase system in type 1 diabetic nephropathy identified by proteomic analysis. 1497 67

Non-enzymatic glycation of proteins is a consequence of hyperglycemia in diabetes and correlates with aging. The aim of the study was to investigate age-related changes in the glycation of human aortic elastin in healthy subjects by two approaches: (1) assessment by fluorescence method of formed in vivo advanced glycation end products (AGEs) of elastins, purified from human aortas, obtained from different age groups; (2) in vitro glycation of elastins from different age groups and investigation of their capacity to form early (by colorimetric nitroblue tetrazolium method) and AGEs (fluorescence method). Human insoluble elastins were prepared from macro- and microscopic unaltered regions of thoracic aortas, obtained from 68 accident victims, distributed in 15 age-groups, using the method of Starcher and Galione. Soluble alpha-elastins were obtained by the method of Partridge et al. The direct assessment of Maillard reaction related fluorescence in the age groups showed increase of the fluorescence with age. The 'young' elastin had the highest capacity to form both fructosamine and AGEs under glycation in vitro. The glycation of 'old' elastin did not increase markedly during the incubation. These results are consistent with the interpretation that because of its long biological half-life, elastin is susceptible to the slow process of glycation and the following modifications would contribute to the age-related changes of connective tissue.
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PMID:Age-related changes in the glycation of human aortic elastin. 1503 19

Aortic elasticity is an important factor in hemodynamic health, and compromised aortic compliance affects not only arterial dynamics but also myocardial function. A variety of pathologic processes (e.g., diabetes, Marfan's syndrome, hypertension) can affect aortic elasticity by altering the microstructure and composition of the elastin and collagen fiber networks within the tunica media. Ultrasound tissue characterization techniques can be used to obtain direct measurements of the stiffness coefficients of aorta by measurement of the speed of sound in specific directions. In this study we sought to define the contributions of elastin and collagen to the mechanical properties of aortic media by measuring the magnitude and directional dependence of the speed of sound before and after selective isolation of either the collagen or elastin fiber matrix. Formalin-fixed porcine aortas were sectioned for insonification in the circumferential, longitudinal, or radial direction and examined using high-frequency (50 MHz) ultrasound microscopy. Isolation of the collagen or elastin fiber matrices was accomplished through treatment with NaOH or formic acid, respectively. The results suggest that elastin is the primary contributor to aortic medial stiffness in the unloaded state, and that there is relatively little anisotropy in the speed of sound or stiffness in the aortic wall.
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PMID:Ultrasonic delineation of aortic microstructure: the relative contribution of elastin and collagen to aortic elasticity. 1513 13

Atherosclerosis is characterized by inflammatory metabolic change with lipid accumulation in the artery. Atherosclerotic plaque occurs at discrete locations in the arterial system and involves the proliferation of smooth muscle cells (SMCs) together with imbalance of the extracellular matrix elements, elastic fiber in particular. The role of elastin in arterial development and disease was confirmed by generating mice that lack elastin. Thus, elastin is a critical regulatory molecule that regulates the phenotypic modulation, proliferation and migration of SMCs. We estimated that elastin expression and SMC proliferation are coupled inversely: potent stimulators of cell proliferation may potentially inhibit elastin expression and potent inhibitors of cell proliferation can stimulate elastin expression. Moreover, elastin was found to be expressed maximally at the G(0) and minimally at the G(2)/M phase during the cell cycle, suggesting that its expression is regulated by the cell growth state. The elastin peptide VPGVG enhanced SMC proliferation, resulting in the reduction of elastin expression. The inhibition of elastin expression by elastin fragments may be reflected in the negative feedback regulatory mechanism. The relationship between cell proliferation and elastin expression may be changed in atherosclerosis. Areas of atherosclerotic plaque show abnormality of elasticity and permeability from the viewpoint of the physiological function of the arterial wall. The etiology was estimated to be that cholesterol and calcium are deposited on the elastic fiber, resulting in decreased elastin synthesis and cross-linking formation. In addition, these dysfunctions of elastin fiber are also associated, in that the down-regulation of elastin and its related components (fibrillin-1 and lysyl oxidase) are directly related to calcification in SMCs. The denatured arterial elastin by cholesterol and calcium accumulation was also susceptible to proteolytic enzymes such as elastase and matrix metalloproteinase (MMP). Therefore, metabolic change in elastic fiber induces decreased elasticity and is associated with essential hypertension. Vitamin K(2) is used in drug therapy against atherosclerosis, or calcification in diabetes mellitus or dialysis, due to its promotion of the carboxylation of the matrix Gla protein.
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PMID:Atherosclerosis and matrix dystrophy. 1555 5

1. Despite over half a century of intensive research, cardiovascular disease remains the leading cause of death world wide. Nevertheless, a number of risk factors for cardiovascular disease have been identified, such as hypertension and serum cholesterol, and therapies targeting such factors are effective in reducing cardiovascular and total mortality. Arterial stiffness is an additional independent risk factor for cardiovascular disease and strategies aimed at lowering arterial stiffness may be effective in reducing cardiovascular risk. However, in order to exploit fully the therapeutic potential of this approach, it is necessary first to understand the physiological and pathophysiological factors regulating the stiffness of the large arteries. 2. Until recently, stiffness was thought to depend largely upon structural components within the arterial wall, such as elastin and collagen and the distending pressure. However, we now recognize that arterial smooth muscle also regulates vessel stiffness and that a number of locally derived and circulating factors, including nitric oxide (NO), endothelin-1 and the natriuretic peptides, contribute to the short-term or functional regulation of large artery stiffness. Changes in the balance between these factors and, in particular, a reduction in NO production may well explain why conditions such as hypercholesterolaemia and diabetes are themselves associated with arterial stiffening before the development of manifest atherosclerosis. 3. The importance of smooth muscle in regulating arterial stiffness suggests that direct pharmacological manipulation of stiffness may be possible, thus providing novel therapeutic strategies to reduce cardiovascular risk. Furthermore, differences in the effect of existing drugs on larger artery stiffness may explain, in part, why some drugs produce better clinical outcomes than others.
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PMID:Arterial stiffness, endothelial function and novel pharmacological approaches. 1556 96

Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.
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PMID:Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. 1560 32

Glycemia is a physiological parameter tightly regulated for an optimal energetic supply to the organism, in spite of variable tissular glucose needs. Physiopathological alteration of glycemic regulation leads to dysfunctions of many cell types. For example, diabetes considerably increases morbidity and mortality linked to cardiovascular pathologies and constitute nowadays a serious public health problem. Many in vivo and in vitro studies have investigated the impact of extracellular glucose concentration on smooth muscle and endothelial cells. Glycemia regulates expression and activity of proteins implicated in various processes, such as vasodilation (eNOS), cellular adherence (ICAM-1, VCAM-1), glucose transport (GLUT-1) or free radical generation. Nuclear receptors of the PPAR (peroxisome proliferator-activated receptors) family which are implicated in glucose and lipid metabolism control, seem to have direct vascular actions, in the regulation of cellular functions by extracellular glucose, reinforcing their status of pharmacological targets for preservation and improvement of vascular function. More general processes, such as cellular proliferation and cell death, are also influenced by glucose concentration. Concerning the contractile function, hypoglycemia and hyperglycemia modulate vascular reactivity while acting on the vasoactive substances level and the cellular response to these molecules. In particular they act on variation of ionic channels (K+, Ca2+) activity or by interfering with some signaling pathways (NO). For example, the age-dependant vasodilation and endothelial calcium influx induced by elastin peptide are modulated by extracellular glucose levels. In conclusion, abnormal chronic variations of circulating glucose levels seem to be directly responsible for endothelial and smooth muscle cell dysfunction in the pathogenesis of cardiovascular abnormalities of patients presenting glycemia dysregulations.
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PMID:[Effect of glucose concentration on vascular function in aging. Action on calcium fluxes and vasomotricity induced by elastin peptides]. 1566 45


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