Cattelan Arianna, Ceolotto Giulio, Bova Sergio, Albiero Mattia, Kuppusamy Maniselvan, De Martin Sara, Semplicini Andrea, Fadini Gian Paolo, de Kreutzenberg Saula Vigili, Avogaro Angelo
Department of Medicine-DIMED, University of Padova, Italy.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy.
Vascul Pharmacol. 2015 Jul;70:35-44. doi: 10.1016/j.vph.2015.02.004. Epub 2015 Apr 9.
Ischemia-reperfusion (IR) leads to severe organ injury and dysfunction. Sirtuins (SIRTs) are a family of histone deacetylases (HDACs) that require nicotinamide adenine dinucleotide (NAD(+)) for the deacetylation reaction. SIRTs play a major role in counteracting cellular stress and apoptosis. This study aimed to investigate the mechanisms of heart protection against apoptosis by SIRTs and the molecular pathways involved in SIRTs regulation and function in a rat model of IR injury. Hearts of male Wistar-Kyoto rats were subjected to 30-min ischemia followed by reperfusion up to 6h. IR increased cardiomyocyte apoptosis; the cleavage of caspase 3, induced a transient upregulation of SIRT1 and downregulation of SIRT6 expression, but decreased SIRT1 activity and reduced NAD(+) content. IR also increased forkhead box protein O1 (FoxO1) expression and FoxO1 binding to SIRT1 promoter region. Resveratrol restored SIRT1 activity and NAD(+) level by an AMPK-dependent mechanism, reduced cardiomyocyte apoptosis, and attenuated caspase 3 cleavage via heat shock factor-1 deacetylation and heat shock protein (HSP) expression upregulation. Our data show new potential molecular mechanisms of up and downstream regulation of SIRT1 in IR. The interplay among FoxO1, SIRT1, NAD(+), AMPK, HSP, and SIRT6 depicts a complex molecular network that protects the heart from apoptosis during IR and may be susceptible to therapeutic interventions.
缺血再灌注（IR）会导致严重的器官损伤和功能障碍。沉默调节蛋白（SIRTs）是一类组蛋白脱乙酰酶（HDACs），其脱乙酰化反应需要烟酰胺腺嘌呤二核苷酸（NAD(+)）。SIRTs在抵抗细胞应激和凋亡中起主要作用。本研究旨在探讨在IR损伤大鼠模型中，SIRTs对心脏抗凋亡的保护机制以及SIRTs调节和功能所涉及的分子途径。雄性Wistar-Kyoto大鼠心脏经历30分钟缺血，随后再灌注长达6小时。IR增加了心肌细胞凋亡；半胱天冬酶3的裂解，诱导了SIRT1的短暂上调和SIRT6表达的下调，但降低了SIRT1活性并降低了NAD(+)含量。IR还增加了叉头框蛋白O1（FoxO1）的表达以及FoxO1与SIRT1启动子区域的结合。白藜芦醇通过一种依赖AMPK的机制恢复了SIRT1活性和NAD(+)水平，减少了心肌细胞凋亡，并通过热休克因子-1去乙酰化和热休克蛋白（HSP）表达上调减弱了半胱天冬酶3的裂解。我们的数据显示了IR中SIRT1上下游调节的新潜在分子机制。FoxO1、SIRT1、NAD(+)、AMPK、HSP和SIRT6之间的相互作用描绘了一个复杂的分子网络，该网络在IR期间保护心脏免受凋亡，并且可能易于进行治疗干预。
