Cardiomyocyte-specific GCN5L1 ablation aggravates Heart Failure with Preserved Ejection Fraction

Background: Heart Failure with Preserved Ejection Fraction (HFpEF) contributes to 50 % of heart failure patients, and is the leading cause of death globally. GCN5L1 is a mitochondrial acetyltransferase protein that promotes mitochondrial protein acetylation, and its expression increases with aging and metabolic disease. However, the role of cardiomyocyte-specific GCN5L1 deletion in HFpEF has not yet been explored. The current study investigates the role of cardiac-specific GCN5L1 ablation in the development and progression of HFpEF. Hypothesis: Investigate the role of cardiomyocyte-specific GCN5L1 ablation on Heart Failure with Preserved Ejection Fraction. Methods: HFpEF was induced in WT and cardiac-specific GCN5L1 KO male mice by feeding them a high-fat diet (HFD; 60 % Kcal from fat) and N w -nitro-L-arginine methyl ester (L-NAME) (0.5 g/L) for 15 weeks. The body weight of the experimental animals was monitored throughout the study. We measured fasting blood glucose levels, glucose tolerance, and cardiac function by 2D-echocardiography after 8 and 15 weeks. We also measured vital organ morphometry (ex., heart weight, liver weight, lung weight) at the end of the study. We assessed cardiac morphology and fibrosis using H&E and Masson’s trichrome staining. We also performed transcriptomics and metabolomics analyses of heart tissues across the experimental groups to identify prominently affected pathways due to cardiac-specific GCN5L1 deletion. Results: HFD-L-NAME feeding for 15 weeks significantly increased body weight compared to chow diet-fed mice, and cardiac-specific GCN5L1 KO further exacerbated this parameter. In WT mice, insulin resistance was not observed at 8 weeks, but was evident at 15 weeks. In contrast, GCN5L1 KO mice displayed significant insulin resistance at both 8 and 15 weeks of HFD-L-NAME treatment. Systolic heart function was not affected at either time point in both genotypes. However, diastolic function (i.e., Increased E/e’ and Isovolumic Relaxation Time (IVRT)) was significantly compromised in WT HFD-L-NAME treated mice compared to WT chow mice. Diastolic dysfunction was further worsened in GCN5L1 KO mice fed with HFD-L-NAME relative to WT mice. We did not observe a significant increase in heart, lung, or liver weight in WT mice fed with HFD-L-NAME, but GCN5L1 KO HFD-L-NAME mice displayed significantly increased organ weights. Cardiac fibrosis, especially interstitial fibrosis, was greater in WT mice fed with HFD-LNAME and increased in GCN5L1 KO animals fed the same diet. Our transcriptomic, metabolic and protein expression studies revealed that one-carbon metabolism is particularly disrupted in GCN5L1 KO mice on an HFD-L-NAME diet. Conclusion: We conclude that cardiac-specific GCN5L1 KO exacerbates HFD-L-NAME-induced cardiac diastolic dysfunction by promoting insulin resistance and disrupting cardiac one-carbon metabolism. This work was supported by 23EIA1037834 (AHA), R01HL147861 (NIH/NHLBI), R01HL156874 (NIH/NHLBI). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.