elastin and Hyperglycemia

The microangiopathy under hyperglycemia and diabetes develops only in the microcirculation component of circulatory system. In this area considerable amount of pericytes is concentrated. These cells contain myofibrils and in circulatory mode envelop capillaries being situated on the outside of basilemma. It is possible that in a phylogenetic sense this is the earliest functional unity of endothelium monolayer as a pacemaker and pericytes as contractile elements which are the earliest "propeller" because of implementing the function of advancement of lymph, hemolymph and blood in capillaries. Probably, endothelium and pericytes formed the first variation of peristaltic "pump" for the purpose of blood advancement longwise of capillaries. Most probably, the state of distal part of arterial race (muscular type arterioles) impact the parameters of proximal part of arterial race (elastic type arterioles) and myocardium itself in the same extent as the state of "pump" in capillaries, endothelium and pericytes function impact the function of local peristaltic pumps (muscular type arterioles) in paracrine cenosis. It is supposed that the pericytes are the regulators of physical, hydraulic factor of activation of biologic reaction of transcitosis--excretion of nutrients and humoral mediators from capillaries to the pool of intercellular medium to perform the biologic function of homeostasis. Hyperglycemia, glycotoxins formation, bivalent substances (glyoxal, methilglyoxal, malonic dialdehyde) reacting simultaneously by both ends of molecule result in formation within collagen of areolar tissue of short transversal cross-links (glycosylation end product) which significantly increase rigidity (hardness) of capillary wall. In these conditions, myofibrils of pericytes no longer form directed deformation of capillary wall to effect peristalsis and advancement of hemolymph (blood later on) along capillaries according the synthesis of monolayer endothelium NO as a dilatation factor. This is the cause of blood circulation disturbance on the level of exchange capillaries and formation of chronic hypoxemia resulting in the only increase of rate of glycosylation chemical reaction. The microangiopathy is formed in the cells and tissues in an integrated pool of intercellular medium and never occurs in the cerebrospinal fluid pool where no hyperglycemia develops.

Topics: Arterioles; Capillaries; Cell Communication; Collagen; Diabetes Mellitus; Diabetic Angiopathies; Elastin; Extracellular Matrix; Glycation End Products, Advanced; Glycosylation; Humans; Hyperglycemia; Hypoxia; Pericytes

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.

Topics: Aging; Animals; Apoptosis; Blood Glucose; Blood Vessels; Calcium Signaling; Cell Adhesion; Cell Division; Diabetes Mellitus; Elastin; Endothelium, Vascular; Gene Expression Regulation; Glucose; Humans; Hyperglycemia; Ion Channels; Muscle, Smooth, Vascular; Peroxisome Proliferators; Signal Transduction; Vasodilation

Elastin is a key elastomeric protein responsible for the elasticity of many organs, including heart, skin, and blood vessels. Due to its intrinsic long life and low turnover rate, damage in elastin induced by pathophysiological conditions, such as hypercalcemia and hyperglycemia, accumulates during biological aging and in aging-associated diseases, such as diabetes mellitus and atherosclerosis. Prior studies have shown that calcification induced by hypercalcemia deteriorates the function of aortic tissues. Glycation of elastin is triggered by hyperglycemia and associated with elastic tissue damage and loss of mechanical functions via the accumulation of advanced glycation end products. To evaluate the effects on elastin's structural conformations and elasticity by hypercalcemia and hyperglycemia at the molecular scale, we perform classical atomistic and steered molecular dynamics simulations on tropoelastin, the soluble precursor of elastin, under different conditions. We characterize the interaction sites of glucose and calcium and associated structural conformational changes. Additionally, we find that elevated levels of calcium ions and glucose hinder the extensibility of tropoelastin by rearranging structural domains and altering hydrogen bonding patterns, respectively. Overall, our investigation helps to reveal the behavior of tropoelastin and the biomechanics of elastin biomaterials in these physiological environments. STATEMENT OF SIGNIFICANCE: Elastin is a key component of elastic fibers which endow many important tissues and organs, from arteries and veins, to skin and heart, with strength and elasticity. During aging and aging-associated diseases, such as diabetes mellitus and atherosclerosis, physicochemical stressors, including hypercalcemia and hyperglycemia, induce accumulated irreversible damage in elastin, and consequently alter mechanical function. Yet, molecular mechanisms associated with these processes are still poorly understood. Here, we present the first study on how these changes in elastin structure and extensibility are induced by hypercalcemia and hyperglycemia at the molecular scale, revealing the essential roles that calcium and glucose play in triggering structural alterations and mechanical stiffness. Our findings yield critical insights into the first steps of hypercalcemia- and hyperglycemia-mediated aging.

Topics: Atherosclerosis; Calcium; Elastin; Glucose; Humans; Hypercalcemia; Hyperglycemia; Tropoelastin

Diabetes and respiratory diseases are frequently comorbid conditions. However, the mechanistic links between hyperglycemia and lung dysfunction are not entirely understood. This study examined the effects of high sucrose intake on lung mechanics and alveolar septal composition and tested voluntary activity as an intervention strategy. C57BL/6N mice were fed a control diet (CD, 7% sucrose) or a high sucrose diet (HSD, 35% sucrose). Some animals had access to running wheels (voluntary active; CD-A, HSD-A). After 30 weeks, lung mechanics were assessed, left lungs were used for stereological analysis and right lungs for protein expression measurement. HSD resulted in hyperglycemia and higher static compliance compared to CD. Lung and septal volumes were increased and the septal ratio of elastic-to-collagen fibers was decreased despite normal alveolar epithelial volumes. Elastic fibers appeared more loosely arranged accompanied by an increase in elastin protein expression. Voluntary activity prevented hyperglycemia in HSD-fed mice. The parenchymal airspace volume, but not the septal volume, was increased. The septal extracellular matrix (ECM) composition together with the protein expression of ECM components was similar to control levels in the HSD-A-group. In conclusion, HSD was associated with elastic fiber remodeling and reduced pulmonary elasticity. Voluntary activity alleviated HSD-induced ECM alterations, possibly by preventing hyperglycemia.

Topics: Animals; Collagen; Elastic Tissue; Elastin; Extracellular Matrix; Gene Expression Profiling; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Pulmonary Alveoli; Running; Sucrose

Although it has long been established that the extracellular matrix acts as a mechanical support, its degradation products, which mainly accumulate during aging, have also been demonstrated to play an important role in cell physiology and the development of cardiovascular and metabolic diseases. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels on the β-chain of the IR and reduction of IR signaling. In conclusion, this is the first study to demonstrate that EDPs, which mainly accumulate with aging, may be involved in the insidious development of IRES.

Topics: Animals; Elastin; Energy Metabolism; Hyperglycemia; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; N-Acetylneuraminic Acid; Neuraminidase; Oligopeptides; Peptide Fragments; Receptor, Insulin; Receptors, Cell Surface

A novel amino acid named aldosine was isolated from acid hydrolysates of bovine aorta elastin. The mass spectral analysis of aldosine indicated a parent compound with a mass of 256 (C12H20N2O4). From the structure identified by spectroscopy of aldosine and its derivatives, it was deduced that aldosine was derived from aldol crosslink and dehydromerodesmosine of elastin and collagen. The aldosine content in aorta of newborn rats was very low, but increased markedly with growth. After maturity was reached, the aldosine content decreased. The aldosine content in bovine aorta decreased gradually from 7 months to 16 years of age. Aldosine was also quantified in the aorta and tail tendon of rats in two models of hyperglycemia: diabetes and galactosemia. Hyperglycemias were significantly affected on aldosine content of organs. In both diabetic and galactosemic animals, aldosine was remarkably lower relative to controls (about one-half and one-sixth, respectively).

Topics: Aging; Amino Acids; Animals; Aorta; Cattle; Collagen; Cross-Linking Reagents; Diabetes Mellitus, Experimental; Disease Models, Animal; Elastin; Galactosemias; Hyperglycemia; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Tendons; Tissue Distribution