HO-1代谢产物在糖尿病心肌病中的作用及槲皮素干预机制

The pathogenesis of diabetic cardiomyopathy (DCM) is complex, and oxidative stress throughout exists. In the endogenous antioxidant systems, HO-1 plays a multi-level and multi-channel antioxidant defense by the metabolites (CO, bilirubin, Fe2+) , and it becomes a potential molecular targets for the prevention and control of DCM, but the defense mechanism is unclear. This project intends to establish DCM animal model with streptozotocin, and investigate the role of HO-1/metabolites in oxidative damage of DCM by HO-1 induction/suppression, and than observe the intervention effect by quercetin. We further discuss the effect of HO-1 induction/inhibition and the metabolites as well as the change of cell oxidative damage in the H9c2 cardiac muscle cell line, and preliminarily study the molecular targets of quercetin against high glucose induced myocardial cell oxidative damage by HO-1 inducing. Moreover, related signaling molecules and pathways will be blocked by using RNA transfection/silence and restrain/blockers, and it will reveal HO-1 metabolites against high glucose induced myocardial cell oxidative damage signal pathways and molecular mechanisms accordingly. The study will provide new theoretical and experimental basis for early prevention and nutritional intervention for DCM.

糖尿病心肌病（DCM）发病机制复杂，而氧化应激贯穿始终。内源性抗氧化系统中HO-1可通过其代谢产物（CO、胆红素、Fe2+）发挥多层次、多途径抗氧化防御，成为防治DCM潜在分子靶点，防御机制尚不清楚。本项目拟注射STZ建立DCM动物模型，通过HO-1诱导/抑制，探讨HO-1/代谢产物在DCM心肌氧化损伤中的作用以及天然植物化学物槲皮素的干预效应。以H9c2心肌细胞系为研究对象，探讨HO-1诱导/抑制及各代谢产物作用与阻断下细胞氧化损伤程度的变化，初步确定槲皮素诱导HO-1拮抗高葡萄糖孵育心肌细胞氧化损伤的分子靶点。在此基础上，借助于RNA转染/沉默及各种抑制/阻断剂，揭示槲皮素诱导HO-1及各代谢产物拮抗高葡萄糖暴露下心肌细胞氧化损伤信号通路与分子机制，为DCM早期预防和营养干预提供新的理论和实验依据。

糖尿病心肌病（DCM）发病机制复杂，内源性抗氧化系统中HO-1及其代谢产物尤其是CO可能发挥多层次、多途径抗氧化损伤作用，成为防治DCM潜在分子靶点。本项目以高脂高糖喂养加腹腔链脲霉素（STZ）注射的方法建立DCM动物模型，从动物和细胞水平，探讨天然植物化学物槲皮素对糖尿病心肌损伤的生物学保护效应和HO-1及其代谢产物介导的机制研究。在此基础上，进行了更加深入的研究，探讨了槲皮素干预对糖尿病胰岛β细胞铁死亡和糖尿病早期肝脏铁代谢紊乱对肝脏胰岛素抵抗的影响。研究发现，槲皮素和CO表现出显著的心肌保护效应，减轻了糖尿病心肌的氧化损伤和炎症反应，改善心功能。同时发现，糖尿病小鼠胰腺铁死亡可诱导胰腺胰岛细胞死亡，而槲皮素通过鳌和铁和抗氧化作用减轻胰腺铁死亡。此外，糖尿病小鼠肝细胞铁代谢失调可引起胞内可利用铁缺乏，进而通过诱导内质网应激促进胰岛素抵抗。本研究的开展不仅探讨了槲皮素对糖尿病心肌、胰腺、肝脏等损伤的保护效应，同时研究了HO-1及其代谢产物CO以及铁代谢紊乱等在糖尿病发展中的作用机制，为天然植物化合物用于糖尿病的预防提供了新的理论依据。