Changes in elastin structure and extensibility induced by hypercalcemia and hyperglycemia
Changes in elastin structure and extensibility induced by hypercalcemia and hyperglycemia
复制标题
DOI：
10.1016/j.actbio.2022.03.041
复制
发表时间：
2023-05-12
影响因子：
9.7
通讯作者：
Tarakanova，Anna
中科院分区：
文献类型：
--
作者：
Yang，Chengeng;Weiss，Anthony S.;Tarakanova，Anna
弹性蛋白是一种关键的弹性蛋白，负责许多器官的弹性，包括心脏，皮肤和血管。由于其固有的长寿命和低周转率，由病理生理条件（如高钙血症和高血糖症）诱导的弹性蛋白损伤在生物老化期间和老化相关疾病（如糖尿病和动脉粥样硬化）中积累。以往的研究表明，高钙血症引起的钙化恶化主动脉组织的功能。弹性蛋白的糖基化由高血糖症触发，并与弹性组织损伤和通过晚期糖基化终产物的积累而丧失机械功能相关。为了评估高钙血症和高血糖症在分子水平上对弹性蛋白结构构象和弹性的影响，我们在不同条件下对弹性蛋白的可溶性前体原弹性蛋白进行了经典的原子和操纵分子动力学模拟。我们表征葡萄糖和钙的相互作用位点和相关的结构构象变化。此外，我们发现，钙离子和葡萄糖的水平升高阻碍了弹性蛋白原的延伸性，通过重排结构域和改变氢键模式，分别。总的来说，我们的研究有助于揭示弹性蛋白原的行为和弹性蛋白生物材料在这些生理环境中的生物力学。重要性声明弹性蛋白是弹性纤维的关键成分，弹性纤维赋予许多重要的组织和器官，从动脉和静脉，皮肤和心脏，强度和弹性。在衰老和衰老相关疾病，如糖尿病和动脉粥样硬化，物理化学应激，包括高钙血症和高血糖症，诱导累积的不可逆损伤的弹性蛋白，并因此改变机械功能。然而，与这些过程相关的分子机制仍然知之甚少。在这里，我们提出了第一个研究如何在弹性蛋白的结构和延展性的这些变化是由高钙血症和高血糖症在分子水平上引起的，揭示了钙和葡萄糖在触发结构改变和机械刚度中发挥的重要作用。我们的研究结果对高钙血症和高血糖介导的衰老的第一步产生了重要的见解。
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 significanceElastin 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.