Ogfod1 deletion increases cardiac beta-alanine levels and protects mice against ischaemia– reperfusion injury

作者：Michael Harris, Junhui Sun, Karen J. Keeran, Angel Aponte, Komudi Singh, Danielle Springer, Marjan Guček, Mehdi Pirooznia, Matthew E. Cockman, Elizabeth Murphy, Leslie Kennedy · 发表于：Cardiovascular Research · 年份：2021 · DOI：10.1093/cvr/cvab323 · 被引用次数：14 · 研究领域：Biochemical effects in animals、Endoplasmic Reticulum Stress and Disease、Heme Oxygenase-1 and Carbon Monoxide

AIMS: Prolyl hydroxylation is a post-translational modification that regulates protein stability, turnover, and activity. The proteins that catalyze prolyl hydroxylation belong to the 2-oxoglutarate- and iron-dependent oxygenase family of proteins. 2-oxoglutarate- and iron-dependent oxygenase domain-containing protein 1 (Ogfod1), which hydroxylates a proline in ribosomal protein s23 is a newly described member of this family. The aims of this study were to investigate roles for Ogfod1 in the heart, and in the heart's response to stress. METHODS AND RESULTS: We isolated hearts from wild-type (WT) and Ogfod1 knockout (KO) mice and performed quantitative proteomics using tandem mass Tag labelling coupled to liquid chromatography and tandem mass spectrometry (LC-MS/MS) to identify protein changes. Ingenuity pathway analysis identified 'Urate Biosynthesis/Inosine 5'-phosphate Degradation' and 'Purine Nucleotides Degradation II (Aerobic)' as the most significantly enriched pathways. We performed metabolomics analysis and found that both purine and pyrimidine pathways were altered with the purine nucleotide inosine 5'-monophosphate showing a 3.5-fold enrichment in KO hearts (P = 0.011) and the pyrimidine catabolism product beta-alanine showing a 1.7-fold enrichment in KO hearts (P = 0.014). As changes in these pathways have been shown to contribute to cardioprotection, we subjected isolated perfused hearts to ischaemia and reperfusion (I/R). KO hearts showed a 41.4% decrease in infa...