NF-κB调控内质网应激促进心肌细胞衰老的机制研究

Aging is one of the major risk factors for cardiovascular disease. Recent studies have shown that the activity of NF-kappa B increases significantly with age, but the role and mechanism of NF-kappa B in cardiac aging are still unclear. Our previous studies have shown that, like other tissues, aging hearts also exhibit increased activity of NF-kappa B, and cardiac specific inhibition of NF-kappa B can reduce age-related myocardial hypertrophy. Meanwhile, we also found that endoplasmic reticulum stress, as a protective strategy against harmful effects, gradually declines with age. In order to further study the specific role of NF-kappa B in cardiac aging and its molecular mechanism, this project intends to use cardiac-specific overexpression mutant I-kappa B alpha protein (Tg-IkBαS32A,S36A) to inhibit the activity of NF-kappa B. Echocardiography, histopathological staining and immunofluorescence were used to detecte the effects of NF-kappa B on aging-related myocardial remodeling, cardiac dysfunction, myocardial fibrosis and apoptosis of cardiomyocyte. WB, RT-PCT, EMSA were used to confirm that NF-kappa B promote cardiomyocyte senescence through endoplasmic reticulum stress pathway, reveals the molecular mechanism of cardiac aging, and provides a new theoretical basis for the treatment of cardiovascular diseases in the elderly.

老年是心血管疾病的主要危险因素之一。最新研究显示，NF-κB活性随着年龄的增长明显增加，但其在心脏衰老中的作用及其机制仍不明确。我们前期研究显示，与其他组织一样，老化的心脏也呈现出增加的NF-κB活性，而心脏特异性抑制NF-κB可减少衰老引起心肌肥大。同时我们还发现，内质网应激作为机体对抗有害影响的保护策略，其功能也随着年龄的增长而逐渐下降。为了深入研究NF-κB在心脏衰老中的具体作用及其分子机制，本项目拟应用心脏特异性过表达突变IκBα蛋白(Tg-IkBαS32A,S36A)抑制NF-κB活性，通过心脏超声、组织病理学染色，免疫荧光等检测NF-κB对衰老相关的心肌重塑、心脏功能障碍、心肌纤维化及心肌细胞凋亡的影响，并通过WB，RT-PCT，EMSA等方法确证NF-κB通过内质网应激信号途径对上述作用进行调控，揭示心脏衰老的分子机制，为老年心血管疾病的治疗提供新的理论依据。

核转录因子NF-κB在衰老过程中具有重要调控作用。本课题在既往研究的基础上，通过心脏特异性抑制NF-κB活性评估NF-κB对衰老相关心脏损伤的影响。初步明确了抑制NF-κB活性可以减少衰老引起的心肌肥大，心功能障碍、心肌重构、心肌细胞凋以及心脏纤维化，并可通过调控P53-P21通路延缓心肌细胞衰老。进一步研究还发现，NF-κB对心脏衰老的调控作用可能与内质网应激相关。为了进一步寻找延缓心脏衰老的有效措施，我们通过对中年小鼠小剂量补充叶酸至老年小鼠，结果发现，补充叶酸可以通过调控内质网应激改善老年相关的心脏重构和功能障碍，并在老龄化过程中减少心肌细胞衰老。综合上述结果，本研究结果不仅完善了心肌衰老的药物治疗，还为老年心力衰竭患者提供新的治疗理论基础和实验依据。