衰老心肌缺血易损性调节新机制：NR-SIRT3改善线粒体生物合成及线粒体自噬

The heart is more vulnerable to ischemia reperfusion injury with aging. When the challenge of aging is becoming increasingly serious today, it is urgent to explore the mechanisms and effective interventions of aging-related vulnerability to myocardial ischemia reperfusion injury. The dysfunction of mitochondrial biogenesis and accumulation of defective mitochondria are the core features of aged myocardium, while it is unclear that whether they are important factors in myocardial ischemia reperfusion injury. It was newly reported that nicotinamide riboside (NR) can protect mitochondria by activating mitochondrial deacetylase SIRT3. Our preliminary experiments had found that NR could improve mitochondrial biogenesis and regulate mitophagy which was the major way to eliminate the damaged mitochondria. So we speculated that NR could protect aging myocardium from ischemia reperfusion injury, though improving the dysfunction of mitochondrial biogenesis and accumulation of defective mitochondria. Thus, our present projects strive to utilize transgenic mouse model and cell transfection to unveil: NR activate SIRT3 through increasing cell NAD+ level, and lead to mitochondria biogenesis by acetylate PGC-1α as well as mitophagy by acetylate p53. We aim at confirming the new mechanisms in aging-related myocardial ischemic vulnerability, which is that NR improves mitochondria biogenesis and mitophagy through SIRT3. It will provide important theoretical basis for new therapy of aging-related myocardial ischemic injury.

衰老导致心肌抗缺血能力明显下降，在老龄化挑战日趋严峻的今天，研究衰老心肌缺血易损性增高的分子机制及防治措施尤为迫切。线粒体合成障碍和缺陷线粒体堆积是衰老心肌的重要特征，是否参与缺血易损性增高尚不清楚。最新研究表明，烟酰胺核糖（NR）可通过活化线粒体去乙酰化酶SIRT3，改善线粒体功能。我们预实验结果证实：NR可促进衰老心肌新生线粒体的合成及线粒体自噬而清除受损线粒体。基于此，我们推测，NR可能通过调节线粒体合成障碍和缺陷线粒体堆积，降低衰老心肌缺血易损性。本研究拟通过基因敲除小鼠动物模型及细胞转染相结合的方法阐明：NR通过增加细胞内NAD+激活SIRT3，一方面促进PGC-1α乙酰化调节的线粒体合成，另一方面促进p53乙酰化调节的受损线粒体的自噬清除，以证实“NR-SIRT3改善线粒体生物合成及线粒体自噬”这一衰老心肌缺血易损性调节新机制，为老年缺血性心脏病治疗新靶点提供理论依据。

衰老导致心肌抗缺血能力明显下降，线粒体合成障碍和缺陷线粒体堆积是衰老心肌的重要特征，是否参与缺血易损性增高尚不清楚。最新研究表明，烟酰胺核糖（NR）可通过活化线粒体去乙酰化酶SIRT3，改善线粒体功能。课题组前期研究证实：NR可促进衰老心肌新生线粒体的合成及线粒体自噬而清除受损线粒体。本课题组提出如下假说：NR可能通过调节线粒体合成障碍和缺陷线粒体堆积，降低衰老心肌缺血易损性。本课题按照课题规划，分别建立成年/老年小鼠心肌缺血再灌注模型和心肌细胞缺氧/复氧模型，在细胞和动物两个层面分别证实了课题假说的内容，烟酰胺核糖（NR）能通过NAD+激活Sirt3，一方面通过p53调节线粒体自噬，另一方面通过PGC-1α调节线粒体合成，最终改善小鼠心肌I/R损伤。本课题立足于改善心肌缺血/再灌注（I/R）损伤，系统研究了维生素B3类似物NR与心肌I/R损伤的相互关系，阐明线粒体自噬及线粒体合成在此过程中所起作用。并通过基因技术和药物干预，确定NR通过Sirt3-p53/PGC-1α改善心肌I/R损伤的部分相关作用机制，为心肌I/R损伤的发生机制研究提供了基础，也为临床治疗心肌I/R损伤提供了新的思路。