Abstract MP121: Deleting the 2-oxoglutarate- and Iron-dependent Prolyl Hydroxylase Ogfod1 Alters Purine Nucleotide Regulation and is Cardioprotective

Abstract

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 enzymes. A newly-described member of this family is 2-oxoglutarate- and iron-dependent oxygenase domain containing protein 1 (Ogfod1), which catalyzes prolyl hydroxylation of the ribosomal protein s23 (Rps23). To investigate the cardiovascular function of Ogfod1, we isolated hearts from 5 Ogfod1 -WT and 5 Ogfod1 -KO mice and used Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS) to identify proteomic changes. Ingenuity Pathway Analysis (IPA) identified “Purine Nucleotides Degradation II (Aerobic)” ( P = 0.00017) to be one of the most significantly-enriched pathways. We then did metabolomics and found that Inosine 5’-monophosphate (IMP) was 3.5x higher in Ogfod1 -KO hearts ( P = 0.011), further supporting a role for Ogfod1 in regulating purine nucleotide metabolism. Recent evidence has shown that altering purine nucleotide degradation protects against diet-induced obesity and insulin resistance, so we tested this hypothesis in Ogfod1 -KO mice by feeding them high-fat diets. Ogfod1 ablation protects against high-fat diet-induced obesity and insulin resistance. Altering purine nucleotide degradation has also been shown to be protective against cardiac injury, so we tested the hypothesis that Ogfod1 loss protects the heart from ischemia-reperfusion (I/R) injury by subjecting perfused hearts from 6 Ogfod1 -WT and 6 Ogfod1 -KO mice to ischemia and reperfusion and assessed tissue death. We found a 37% decrease in infarct size in Ogfod1 -KO hearts (56% in Ogfod1 -WT and 35% in Ogfod1 -KO, P = 0.0003). In a separate set of experiments, we treated Ogofd1 -KO mice with isoproterenol to induce hypertrophy, and Ogfod1 -KO hearts showed protection against hypertrophic remodeling. Interestingly, OGFOD1 transcripts were up-regulated in human heart failure, indicating a potential role for OGFOD1 in the human failing heart. Altogether, these data show that Ogfod1 deletion alters the myocardial proteome and myocardial metabolism and protects against obesity, insulin sensitivity, I/R injury, and hypertrophy.