Metabolic Remodeling–Driven Dicarbonyl Stress Impairs Mitochondrial Function in Angiotensin II/Phenylephrine-induced Heart Failure with Preserved Ejection Fraction Phenotype

Heart failure (HF) is a highly morbid condition affecting over 60 million people worldwide. Notably, heart failure with preserved ejection fraction (HFpEF) comprises nearly 50% of all HF cases, with increasing prevalence in young populations. The pathophysiology of HFpEF remains incompletely understood, limiting early diagnosis and effective treatment strategies. Emerging evidence indicates that metabolic remodeling and mitochondrial dysfunction in the heart are central contributors to the pathophysiological progression of HFpEF. However, the mechanistic relationship between altered cardiac metabolism and mitochondrial impairment remains poorly defined. In this study, we comprehensively analyzed metabolic remodeling and mitochondrial health in mice with Angiotensin II (AngII)/phenylephrine (PE)-induced HFpEF phenotype, without the confounding effects of multiple stressors, such as obesity and aging. HFpEF-phenotype was induced in 8–10-week-old mice (n=12-15/group) by subcutaneously implanting osmotic pumps to infuse AngII (1.5 μg/g/day) and PE (50 μg/g/day) for 28 days, while Control mice received only a saline infusion. AngII/PE-infused mice recapitulate the characteristic clinical cardiac parameters of HFpEF, including a preserved ejection fraction and an elevated E/E′ ratio. Compared to Control, AngII/PE-infused mice showed significantly reduced mitochondrial respiration, diminished complex II protein levels, impaired mitochondrial supercomplex formation, and decreased mitochondrial calcium retention capacity. Metabolomic analysis of mitochondria revealed increased metabolites of alternative glucose utilization pathways, and reduced fatty acid metabolites, suggesting a metabolic shift from fatty acid oxidation toward reliance on alternative glucose metabolism pathways. AngII/PE elevated dicarbonyl/glycative stress with increased methylglyoxal and advanced glycation end products (AGEs). Mass spectral analysis identified 17 mitochondrial proteins that were significantly glycated in AngII/PE-infused mice compared to controls. Pathway analysis suggests that glycated protein can potentially affect substrate utilization and impair oxidative phosphorylation. Collectively, our findings indicate that metabolic remodeling critically contributes to the increase of dicarbonyl/glycative stress, impairing mitochondrial supercomplexes formation and respiration, as well as mitochondrial calcium retention capacity in the HFpEF heart. The present findings yield novel insights into future promising therapies targeting anti-dicarbonyl/glycation stress and mitochondrial function to improve disease prognosis in HFpEF patients. Fund: NIH R01HL160969) This abstract was presented at the American Physiology Summit 2026 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.