PGC1α在端粒功能障碍小鼠心肌稳态及线粒体能量代谢中的作用

Telomeres are nucleoprotein complexes at chromosome ends that are associated with aging and many degenerative diseases, including cardiovascular diseases. A significant mitochondrial regulator, PGC1α, functions to mediate mitochondrial biogenesis and lipometabolism. Recent study showed that telomere dysfunction stimulated p53 up-regulation which in turn repressed PGC-1αpromoter,thereby destablising cardiac homeostasis and function.In preliminary studies using angiotensin II induced-cardiac impaired Terc-/- mice,we found a down-regulation of mRNA level of PGC1α and NRF-1 in heart, while TGF-1β and Col-1α were significantly up-regulated,indicating cardiac function deteriorates and tends to be impaired in telomere dysfunctional individual under stress conditions, whilst PGC1α represents as one potential therapeutic target. However, whether a causal role of PGC1α is validated in cardiac impairment/cardiac function alteration, and whether up-regulation of PGC1α can enhance the cardiac performance in the setting of telomere dysfunction remain elusive.To address these questions, we have established Rosa26-flox-stop-flox-PGC1α conditional knock-in mice. By further crossing with cardiomyocyte-specific αMHCcre mice and Terc-/- mice, a third generation of Terc-/- PGC1α αMHCcre triple transgenic mouse model is generated and used to examine the effect of PGC1α on myocardial mitochondrial homeostasis and ventricular remodelling. The causality between PGC1α and cardiac impairment in Terc-/- mice is going to be investigated, thus providing crucial experimental evidence for the prevention and treatment of cardiovascular diseases and translational medical research.

端粒与多种退行性疾病有关，包括心脏的损伤病变。PGC1α作为线粒体功能的主要调节者，对线粒体稳态具有重要作用。最新研究表明，端粒功能障碍小鼠通过上调p53抑制PGC1α启动子转录活性，进而影响心脏稳态及功能。前期我们利用血管紧张素II灌注诱导端粒功能障碍小鼠心脏损伤,发现心脏中PGC1α较对照明显下调，而TGF-1β、Col-1α等显著增加，提示端粒功能障碍小鼠心脏应激功能下降更易受损，而PGC1α可能是潜在的治疗靶点。然而，端粒功能障碍背景下PGC1α与心功能改变是否具有因果关系，上调PGC1α能否提高心肌功能尚不清楚。为此，我们构建了条件性基因敲入小鼠，并与心肌特异Cre小鼠和端粒酶敲除小鼠杂交获得PGC1α心肌特异表达的端粒功能障碍小鼠。本项目拟以此为模型，研究PGC1α对心肌及线粒体稳态维持的影响，阐明PGC1α与端粒功能障碍小鼠心脏损伤直接的因果关系，为临床应用提供实验依据。

端粒与多种退行性疾病有关，包括心脏的损伤病变。PGC1α作为线粒体功能的主要调节者，对线粒体稳态具有重要作用。最新研究表明，端粒功能障碍小鼠通过上调p53抑制PGC1α启动子转录活性，进而影响心脏稳态及功能。前期我们利用血管紧张素II灌注诱导端粒功能障碍小鼠心脏损伤，发现心脏中PGC1α较对照明显下调，而TGF-1β、Col-1α等显著增加，提示端粒功能障碍小鼠心脏应激功能下降更易受损，而PGC1α可能是潜在的治疗靶点。然而，端粒功能障碍背景下PGC1α与心功能改变是否具有因果关系，上调PGC1α能否提高心肌功能尚不清楚。为此，我们构建了条件性基因敲入小鼠，并与心肌特异Cre小鼠和端粒酶敲除小鼠杂交获得PGC1α心肌特异表达的第三代端粒功能障碍小鼠。本项目研究结果提示，心肌特异高表达PGC1a有利于端粒酶功能障碍小鼠在衰老过程中维持心肌和线粒体功能，通过增加线粒体生物合成与稳态，降低ROS和炎症水平，以及减少蛋白聚集体形成，从而显著改善G3小鼠健康寿限。进一步研究发现PGC1a的有益作用部分是通过改善心脏NAD水平实现的，通过长期饲喂NAD前体bNMN可重现PGC1α心肌特异高表达对线粒体及心脏功能的改善作用。值得注意的是，我们发现了一条全新的PGC1a介导的炎症调控途径可以影响体内组织器官NAD水平，从而实现对组织器官衰老的影响。这一有意义的研究发现提示我们通过改善线粒体-炎症-代谢这条轴有望成为延缓心脏衰老甚至抵抗心血管疾病的潜在途径之一，本研究为潜在的临床应用提供实验依据和治疗靶点。