Deleting the Ribosomal Prolyl Hydroxylase OGFOD1 Leads to Protection in Pressure Overload-Induced Cardiac Hypertrophy in Mice

Abstract

Molecular changes occurring in heart failure have largely focused on the transcriptional landscape. However, disparities between transcript and protein abundances emphasize the need to understand proteomic changes occurring in heart failure as well the mechanisms governing these changes. Post-translational modifications (PTMs) are a well-known mechanism for regulating protein turnover and activity. A lesser-known enzyme that catalyzes the addition of PTMs on the translational machinery is 2-oxoglutarate- and Fe2+-dependent oxygenase domain-containing protein 1 (OGFOD1). Our published evidence shows OGFOD1 RNA and protein accumulate in human failing hearts, indicating a potential role for this enzyme in heart disease. Because heart failure can develop from many pathologies, including hypertrophy, we investigated the role of OGFOD1 in cardiac hypertrophy. We induced hypertrophy via pharmacological β-adrenergic stimulation by treating wildtype (WT) and OGFOD1-knockout (KO) mice with isoproterenol (ISO), where we found that KO mice were protected from ISO-induced hypertrophy. Based on our findings that OGFOD1-KO mice are protected in ISO-induced cardiac hypertrophy, we tested the hypothesis that KO mice were protected in pressure overload-induced cardiac hypertrophy mediated via transverse aortic constriction (TAC). WT and KO mice were subjected to sham or TAC surgery, and heart weight-to-tibia length (HW/TL) and heart weight-to-body weight (HW/BW) ratios were used to determine extent of hypertrophy. Additionally, hearts were subjected to histological analysis and stained with Masson’s trichrome to assess fibrosis. KO mouse hearts showed significantly less hypertrophy than WT hearts after 2 weeks of TAC according to both HW/TL and HW/BW ratios. KO mice were also protected against cardiac fibrosis. To identify translational changes mediating this protection, future studies will focus on utilizing ribosome profiling to identify actively-translated transcripts whose synthesis is regulated by OGFOD1-mediated prolyl hydroxylation. Results from these studies will provide important mechanistic insight into the therapeutic potential of OGFOD1 in human disease. NHLBI-NIH Intramural Research Program (ZO1-HL002066). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.