OR16-04 Protective effects of ketogenic diet on aldosterone-induced atherosclerosis in ApoE-/- mice

Abstract Disclosure: A. Armani: None. V. Marzolla: None. C. Mammi: None. L. Vitiello: None. E. Bellucci: None. C. Quattrini: None. M. Lombardo: None. A. Feraco: None. S. Gorini: None. M. Caprio: None. Elevated aldosterone (Aldo) levels are associated with increased cardiovascular risk. In ApoE-/- mice prone to developing atherosclerosis, Aldo has been observed to accelerate disease progression. Ketogenic diets have gained attention for the treatment of obesity, metabolic associated steatotic liver disease (MASLD) and type 2 diabetes, and this study aims to investigate the potential of this dietary regimen to counteract plaque formation in a mouse model of atherosclerosis stimulated by Aldo. Nine-week-old ApoE-/-mice were fed either a ketogenic diet (KD; 90.5% kcal from fat, 0.4% kcal from carbohydrates, 9.1% kcal from protein) or a high-fat control diet (HFD; 42% kcal from fat, 42.7% kcal from carbohydrates, 15.2% kcal from protein) and treated with Aldo (6 μg/mouse/day) or vehicle via osmotic minipumps. Both diets had comparable cholesterol content. After four weeks, we analyzed atherosclerotic plaque size, lipid and collagen content. Vascular inflammation was assessed in aortic tissues by evaluating the expression of pro- and anti-inflammatory genes. Plasma samples were collected to analyse potential changes of the profile of lipoprotein subclasses, i.e. low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses and pro-inflammatory cytokines, contributing to increased risk for MASLD and atherosclerosis. At the moment, these analyses are ongoing. In Aldo-treated ApoE-/- mice, KD significantly improved glucose tolerance compared to HFD-fed controls, with a parallel reduction in body weight. β-hydroxybutyrate levels were higher in KD-fed mice. Plasma samples from all the experimental groups Aortic root analysis revealed that Aldo treatment increased plaque development and lipid content in HFD-fed mice. These effects were significantly reduced in KD-fed mice, suggesting a protective role of nutritional ketosis in preventing atherosclerosis. Plaque fibrosis remained unchanged across the experimental groups. Finally, vascular inflammatory marker expression was lower in KD+Aldo mice than in HFD+Aldo mice. In particular, KD reduced the expression of pro-inflammatory markers such as ICAM-1, VCAM-1, IL-6, TNF-α, and MCP-1 with a parallel induction of M2-like macrophage polarization. The findings show that KD is a dietary approach which counteracts atherosclerosis development induced by Aldo in ApoE-/- mice, suggesting that KD may offer a promising strategy to mitigate atherosclerotic plaque formation in subjects with high cardiovascular risk. Presentation: Sunday, July 13, 2025