Changes in elastin structure and extensibility induced by hypercalcemia and hyperglycemia.

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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]