竹节参皂苷IVa通过调控SIRT3改善能量代谢障碍抗糖尿病心肌病的机制研究

Diabetic cardiomyopathy (DCM), with high morbidity and great damage to health, is the leading cause of death in patients with diabetes mellitus (DM). Aralia taibaiensis has been a time-honored, and effective Chinese herbal medicine prescribed for the treatment of DM and heart diseases. Research and development on Aralia taibaiensis is the main task of our research group. We were authorized the license for a kind of hospital preparation, which was comprised of total saponins of Aralia taibaiensis as the main component. We confirmed the effect of total saponins against DCM, and then the biological monomer with the strongest activity, Chikusetsu saponin IVa (C-IVa), was screened out and identified. In our previous study, it has been proved that C-IVa could attenuate the myocardial injury induced by hyperglycemia and generate more energy, which suggested that C-IVa would probably exert anti-DCM effect by improving the energy metabolism. SIRT3 is the key factor of energy balance regulation in mitochondira. In SIRT3-/- mice DCM model, the protective effect of C-IVa was observed to be significantly weakened, which suggested that SIRT3 might participate in the myocardial protection of C-IVa against DCM. Unfortunately, the underlying mechanism is still unclear. Base on these issues, this study is to reveal the myocardial protection of C-IVa agaisnt DCM by activation of SIRT3, and improvement of energy metabolism disorder on the animal, cellular and molecular levels. This research would contribute to theoretical basis for the application of C-IVa, and would provide novel targets for the drug development of DCM.

糖尿病心肌病（DCM）是糖尿病患者的主要致死原因，发病率高，危害性大。太白楤木治疗糖尿病和心脏疾病历史悠久，疗效确切。本课题组长期从事太白楤木的研究和开发，以楤木总皂苷为主要成分制成的医院制剂已获得临床研究批件。我们在证实总皂苷具有抗DCM作用的基础上，从中筛选出活性最强的单体竹节参皂苷IVa（C-IVa）。前期研究表明C-IVa能减轻高糖诱导的心肌损伤，并增加能量生成，提示C-IVa可能通过改善能量代谢发挥抗DCM作用。SIRT3是线粒体调节能量代谢的关键因子。在SIRT3-/-小鼠DCM模型中C-IVa的保护作用被显著削弱，提示SIRT3可能参与了C-IVa的抗DCM作用，但具体机制尚不清楚。基于此，本课题拟从整体、细胞、分子水平揭示C-IVa通过激活SIRT3，改善能量代谢障碍，发挥抗DCM心肌损伤的机制，为C-IVa的应用提供理论依据，也为开发DCM治疗药物提供新靶点。

糖尿病心肌病（Diabetic cardiomyopathy，DCM）是糖尿病患者的主要致死原因，发病率高，危害性大。本课题组前期研究表明竹节参皂苷Ⅳa（Chikusetsu saponin Ⅳa，C-Ⅳa）不仅能抑制氧化应激反应，而且能够减轻糖尿病诱导的心肌损伤，增加高糖诱导损伤心肌细胞中ATP生成，提示C-Ⅳa具有抗DCM作用，并可能与改善能量代谢有关，但具体机制尚不清楚。基于此，本课题从整体、细胞和分子水平进行C-Ⅳa体内外的药效验证和机制研究：首先确证了C-Ⅳa通过改善能量代谢发挥对DCM受损心肌的保护作用；并围绕C-Ⅳa与SIRT3深入探讨，阐明C-Ⅳa通过激活SIRT3，抑制线粒体通透性转换孔（Mitochondrial permeability transition pore，mPTP）开放，改善能量代谢障碍。本课题的研究丰富了C-Ⅳa保护心肌方面的认识，阐明其抗DCM的作用机制，为进一步推广楤木及其有效成分的临床应用奠定理论基础， 同时也为应用现代分子生物学手段揭示中药有效成分防治DCM的科学内涵提供新思路。此外，由于C-Ⅳa不易透过生物膜，口服吸收慢、消除快，口服剂量大等，极大限制了药效发挥，我们对C-Ⅳa制剂进行了初步探索。基于纳米技术，制备了荷载C-Ⅳa的脂质-聚合物杂化纳米体系（Lipid-polymer hybrid nanoparticles as a carrier of Chikusetsu saponin Ⅳa，C-Ⅳa/LPNs），改善C-Ⅳa的吸收，提高抗DCM疗效，为C-Ⅳa的临床应用提供理论依据。