Beijing Institute of Genomics Chinese Academy of Sciences, Beishan Industrial Zone Shenzhen China.
Diabetes and Obesity Center University of Louisville KY.
J Am Heart Assoc. 2022 Jul 5;11(13):e023868. doi: 10.1161/JAHA.121.023868. Epub 2022 Jun 22.
Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.
背景 组氨酰二肽，如肌肽，在哺乳动物心脏中的浓度范围为微摩尔至毫摩尔。这些二肽通过质子缓冲作用促进糖酵解。它们与反应性醛（如丙烯醛）形成共轭物，从而减轻心肌缺血再灌注损伤。尽管这些二肽具有多种功能，但它们在心肌中的作用还缺乏综合理解。
方法和结果 为了确定组氨酰二肽在心脏中的介导反应，我们使用了一种综合的三omics 方法，该方法涉及全基因组 RNA 测序、全局蛋白质组学和无偏代谢组学，以鉴定心脏特异性过表达肌肽合成酶肌肽合酶（Carns）在小鼠中的作用。我们的结果表明，较高的心肌组氨酰二肽水平与几种 microRNA 的水平广泛变化相关，这些 microRNA 靶向收缩蛋白、β-脂肪酸氧化和柠檬酸循环（TCA）酶的表达。全局蛋白质组学分析显示，Carns 转基因心脏中收缩蛋白、β-脂肪酸氧化酶和 TCA 酶的表达丰富。在有氧条件下，Carns 转基因心脏中的短链和长链脂肪酸以及 TCA 中间产物琥珀酸水平较低；而在缺血条件下，脂肪酸和 TCA 中间产物的积累明显减弱。多个数据集的整合表明，β-脂肪酸氧化和 TCA 途径在 Carns 转基因心脏的所有 3 个水平上均表现出相关变化。
结论 综上所述，这些发现揭示了组氨酰二肽在协调调节心肌结构、功能和能量学方面的核心作用。
