Noyan Hossein, El-Mounayri Omar, Isserlin Ruth, Arab Sara, Momen Abdul, Cheng Henry S, Wu Jun, Afroze Talat, Li Ren-Ke, Fish Jason E, Bader Gary D, Husain Mansoor
Division of Experimental Therapeutics, Toronto General Research Institute, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2015 Jun 22;10(6):e0130658. doi: 10.1371/journal.pone.0130658. eCollection 2015.
To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).
Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.
Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.
This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.
了解短期热量限制（CR）产生心脏预处理效应的分子途径。
长期以来，人们认为终身CR可通过多种机制降低心血管疾病的发病率。然而，长期坚持CR生活方式很困难。在此，我们揭示了短期CR所调节的与保护小鼠心脏免受缺血影响相关的途径。
将10 - 12周龄的雄性C57bl/6小鼠随机分为两组，一组给予随意饮食（AL），可自由获取常规食物；另一组为CR组，在通过永久性冠状动脉结扎诱导心肌梗死（MI）前7天，给予少30%的食物，持续7天。在第8天，收集AL组和CR组小鼠的左心室进行蛋白质印迹、mRNA和微小RNA（miR）分析，以确定心脏保护基因表达特征。在另外的分组中，在MI后第2天测量梗死面积、心脏血流动力学以及半胱天冬酶3的蛋白质丰度。
这种短期CR模型具有心脏保护作用，梗死面积减小证明了这一点（18.5±2.4%对26.6±1.7%，每组N = 10；P = 0.01）。MI前的mRNA和miR谱（每组N = 5）确定短期CR调节的基因与昼夜节律时钟、氧化应激、免疫功能、细胞凋亡、代谢、血管生成、细胞骨架和细胞外基质（ECM）相关。MI前的蛋白质印迹显示，CR使磷酸化Akt和GSK3β增加，磷酸化AMPK以及线粒体相关蛋白PGC - 1α、细胞色素C和环氧化酶（COX）IV水平降低，而磷酸化eNOS或MAPK（ERK1/2；p38）水平无差异。CR方案还与梗死心脏中裂解的半胱天冬酶3的蛋白质丰度降低以及心脏功能改善相关。
