Nedvedova Iveta, Kolar David, Neckar Jan, Kalous Martin, Pravenec Michal, Šilhavý Jan, Korenkova Vlasta, Kolar Frantisek, Zurmanova Jitka M
Department of Physiology, Faculty of Science, Charles University, Prague, Czechia.
Institute of Physiology, Czech Academy of Sciences, Prague, Czechia.
Front Endocrinol (Lausanne). 2019 Jan 22;9:809. doi: 10.3389/fendo.2018.00809. eCollection 2018.
Adaptation to continuous normobaric hypoxia (CNH) protects the heart against acute ischemia/reperfusion injury. Recently, we have demonstrated the infarct size-limiting effect of CNH also in hearts of spontaneously hypertensive rats (SHR) and in conplastic SHR-mt strain characterized by the selective replacement of the mitochondrial genome of SHR with that of more ischemia-resistant Brown Norway rats. Importantly, cardioprotective effect of CNH was more pronounced in SHR-mt than in SHR. Thus, here we aimed to identify candidate genes which may contribute to this difference between the strains. Rats were adapted to CNH (FiO 0.1) for 3 weeks or kept at room air as normoxic controls. Screening of 45 transcripts was performed in left ventricles using Biomark Chip. Significant differences between the groups were analyzed by univariate analysis (ANOVA) and the genes contributing to the differences between the strains unmasked by CNH were identified by multivariate analyses (PCA, SOM). ANOVA with Bonferroni correction revealed that transcripts differently affected by CNH in SHR and SHR-mt belong predominantly to lipid metabolism and antioxidant defense. PCA divided four experimental groups into two main clusters corresponding to chronically hypoxic and normoxic groups, and differences between the strains were more pronounced after CNH. Subsequently, the following 14 candidate transcripts were selected by PCA, and confirmed by SOM analyses, that can contribute to the strain differences in cardioprotective phenotype afforded by CNH: Alkaline ceramidase 2 (), Fatty acid translocase (, Aconitase 1 (), Peroxisome proliferator activated receptor gamma (, Hemoxygenase 2 (, Phospholipase A2 group IIA (), Dynamin-related protein (), Protein kinase C epsilon (), Hexokinase 2 (, Sphingomyelin synthase 2 (, Caspase 3 (), Mitofussin 1 (), Phospholipase A2 group V (), and Catalase (). Our data suggest that the stronger cardioprotective phenotype of conplastic SHR-mt strain afforded by CNH is associated with either preventing the drop or increasing the expression of transcripts related to energy metabolism, antioxidant response and mitochondrial dynamics.
适应持续性常压缺氧（CNH）可保护心脏免受急性缺血/再灌注损伤。最近，我们还证明了CNH对自发性高血压大鼠（SHR）心脏以及同基因SHR-mt品系心脏的梗死面积限制作用，SHR-mt品系的特征是选择性地用更耐缺血的棕色挪威大鼠的线粒体基因组替换SHR的线粒体基因组。重要的是，CNH对SHR-mt的心脏保护作用比对SHR更明显。因此，我们旨在鉴定可能导致品系间这种差异的候选基因。将大鼠置于CNH（FiO₂ 0.1）环境中3周，或置于常氧环境作为对照。使用Biomark芯片对左心室中的45个转录本进行筛选。通过单因素分析（方差分析）分析组间的显著差异，并通过多因素分析（主成分分析、自组织映射）鉴定导致CNH揭示的品系间差异的基因。经Bonferroni校正的方差分析显示，在SHR和SHR-mt中受CNH影响不同的转录本主要属于脂质代谢和抗氧化防御。主成分分析将四个实验组分为两个主要聚类，分别对应慢性缺氧组和常氧组，且在CNH处理后品系间的差异更明显。随后，通过主成分分析选择了以下14个候选转录本，并经自组织映射分析确认，这些转录本可能导致CNH所赋予的心脏保护表型的品系差异：碱性神经酰胺酶2、脂肪酸转运蛋白、乌头酸酶1、过氧化物酶体增殖物激活受体γ、血红素加氧酶2、磷脂酶A2 IIA组、动力相关蛋白、蛋白激酶Cε、己糖激酶2、鞘磷脂合酶2、半胱天冬酶3、线粒体融合蛋白1、磷脂酶A2 V组和过氧化氢酶。我们的数据表明，CNH赋予同基因SHR-mt品系更强的心脏保护表型，这与防止能量代谢、抗氧化反应和线粒体动力学相关转录本的下降或增加其表达有关。
