SIRT6强化PDHc活性在衰老心肌缺血再灌注损伤中的作用及机制

衰老导致心肌抵抗缺血/再灌注（I/R）损伤的耐受力显著降低，阐明老年心肌缺血易损机制符合国家重大需求。SIRT6与衰老密切相关，但靶向激活SIRT6在I/R心肌中的生物学功能是悬而未决的问题。我们利用新型SIRT6变构激动剂在人源心肌细胞模型（hiPSC-CM）中发现：SIRT6对心肌丙酮酸脱氢酶复合体（PDHc）存在非磷酸化的激活调控；SIRT6活化后可上调心肌细胞PDHX表达并使PDHA1的K77和K321乙酰化水平降低；激活SIRT6有效减轻衰老心肌I/R损伤。PDHc是优化I/R心肌能量底物代谢的重要靶点，“SIRT6强化PDHc”可能是防治衰老心肌缺血易损的新途径。本课题结合心肌特异性基因干预动物模型从动物-器官-细胞-分子等层面，揭示以SIRT6强化PDHc的“心肌年轻化”策略对I/R心肌的保护作用，为衰老心肌缺血易损的精准干预提供转化研究策略。

Aging leads to a significant reduction in myocardial tolerance to ischemia/reperfusion (I/R) injury. It is necessary to elucidate the mechanism of aging-related myocardial ischemic vulnerability. SIRT6 is closely related to aging-related metabolic disorders, but the biological function of targeted activation SIRT6 in I/R myocardium is an open question. We used a novel SIRT6 allosteric agonist in a human-derived cardiomyocyte model (hiPSC-CM) to find that SIRT6 has non-phosphorylated activation regulation of myocardial pyruvate dehydrogenase complex (PDHc); SIRT6 activation can up-regulate myocardial PDHX expression; the acetylation levels of of PDHA1 in K77 and K321 were reduced; activating SIRT6 effectively reduced I/R injury in aged myocardium. PDHc is an important target for optimizing myocardial energy substrate metabolism, and "SIRT6 enhanced PDHc" may be a new way to prevent aging-related myocardial ischemic vulnerability. This project combined myocardial-specific gene intervention animal models to reveal the regulatory mechanism of SIRT6 on PDHA1 and PDHX from the animal-organ-cell-molecular level; to clarify the internal relationship of post-translational modification of PDHc and myocardial energy metabolism on the ischemic vulnerability of aging heart; to confirmed the cradioprotection against I/R injury by SIRT6 enhancing PDHc to rejuvenate the heart. This study is expected to elucidate the new mechanism of anti-aging of the myocardium, and provide translational research strategies for the precise intervention of aging-related myocardial ischemic vulnerability.