基于线粒体自噬抗代谢重编程效应探讨H2S抑制心脏干细胞早熟性衰老及糖尿病心肌重构的机制

Previous studies have demonstrated that H2S can improve myocardial remodeling in diabetes and is associated with the inhibition of cell aging. However, the underlying mechanism is unclear. The aging of stem cells is related to the reprogramming of metabolites caused by mitochondrial damage (down-regulation of aerobic glycolysis). Meanwhile, Parkin-mediated mitophagy suppresses reprogramming and delays premature aging. It has also been found that H2S can activate mitophagy. Therefore, we put forward the following hypothesis: H2S can improve mitochondrial homeostasis, inhibit metabolic reprogramming of CSCs and induce premature aging through Parkin-mediated mitophagy, eventually improving diabetic myocardial remodeling. The objectives of this project are: (1) to collect clinic-pathological specimens from diabetic patients and to establish T2DM mice and CSCs models; (2) to verify the inhibitory effect of mitophagy on the metabolic reprogramming of CSCs and the secondary premature aging by gene transfection/knockout and siRNA interference; (3) to explore the mechanism of H2S in inhibiting CSCs premature aging and myocardial remodeling in diabetic mice by activating Parkin-mediated mitophagy. This study may elucidate a new mechanism of H2S in improving myocardial remodeling and provide new targets for clinical treatment and prevention.

申请者前期发现H2S可改善糖尿病心肌重构并与抑制细胞衰老有关，但机制不清。最近发现糖尿病心肌病的发生与心脏干细胞(CSCs)衰老有关，而干细胞衰老与线粒体损伤导致的代谢重编程（糖酵解下调）有关，Parkin介导的线粒体自噬（mitophagy）则可抑制代谢重编程并延缓早熟性衰老。已发现H2S可激活mitophagy，故提出假说：H2S可通过Parkin介导的mitophagy改善线粒体稳态，抑制CSCs代谢重编程及其继发的早熟性衰老，进而改善糖尿病心肌重构。课题拟收集临床病理标本并建立T2DM小鼠和培养CSCs模型，以基因转染/敲除和siRNA干扰等证实mitophagy可抑制CSCs代谢重编程及其继发的早熟性衰老，并探讨H2S通过激活Parkin介导的mitophagy抑制CSCs早熟性衰老和糖尿病小鼠心肌重构的机制。本研究有望发现H2S改善糖尿病心肌重构的新机制并提供临床干预的新靶点。

申请者前期发现H2S可改善糖尿病心肌重构并与抑制细胞衰老有关，但机制不清。最近发现心肌细胞衰老与线粒体损伤导致的代谢重编程有关，线粒体自噬（mitophagy）则可抑制代谢重编程并延缓早熟性衰老。已发现H2S可激活mitophagy，故提出假说：H2S可通过mitophagy改善线粒体稳态，抑制心肌细胞代谢重编程及其继发的应激性衰老，进而改善糖尿病心肌重构。课题通过建立T2DM大鼠和培养心肌细胞模型，以基因转染/敲除和siRNA干扰等证实mitophagy可抑制心肌细胞代谢重编程及其继发的应激性衰老，并探讨H2S通过激活mitophagy抑制心肌细胞衰老和糖尿病大鼠心肌重构的机制。本研究旨在发现H2S改善糖尿病心肌重构的新机制并寻找临床干预的新靶点。项目研究发现：糖代谢性紊乱可导致大鼠心肌纤维化，并与自噬障碍有关，而H2S可通过改善线粒体自噬障碍抑制心肌细胞衰老，进而改善2型糖尿病大鼠心肌纤维化，其机制可能与上调Sirt1有关。高糖刺激可诱发心肌细胞衰老，而H2S可通过SIRT6/AMPK通路抑制细胞衰老及线粒体代谢紊乱，进而改善糖尿病大鼠心肌纤维化；研究同时也发现高同型半胱氨酸氨酸以及高尿毒症毒素也同样可诱发心肌纤维化，并与线粒体自噬障碍及心肌细胞应激性衰老有关，而线粒体靶向性H2S供体AP39可改善高同型半胱氨酸氨酸以及高尿毒症毒素诱发的大鼠心肌纤维化，其内在机制可能与其激活线粒体自噬并抑制线粒体重构及心肌细胞衰老有关。本研究显示线粒体内H2S稳态参与代谢紊乱环境应激下的心肌细胞应激性衰老的调控机制，而重建线粒体内H2S稳态拮抗应激性细胞衰老很可能是改善心肌重构的有效靶点。本研究有助于发现代谢紊乱诱发心肌纤维化的新机制，并找到代谢性心血管病的干预新靶点和防治新策略，故具有重要的科学意义。