Mechanisms underlying the future development of CVD in mothers with GDM were investigated using a mouse model of GDM that mimics the condition observed in human GDM. Examining the aorta in the later life of the GDM model reveals increased arterial stiffness and endothelin activation associated with vascular remodeling. In addition, kinome analysis reveals suppressed cardiac NO/cGMP/PRKG and impaired AMPK-SIRT1 signaling pathways, which corroborate the impaired ventricular relaxation observed in later life in GDM mothers.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly associated with the development of cardiovascular disease (CVD); however, the mechanisms responsible are currently unknown. We have developed a model of MASLD due to the loss of hepatocyte peroxisome proliferator-activated receptor α (PPARα^HEPKO). We found that plasma beta-hydroxybutyrate (BHOB) levels were significantly reduced in PPARα^HEPKO mice and aimed to investigate the therapeutic potential of restoring BHOB levels in the development of CVD in these mice. Thirty-week-old PPARα^HEPKO and control PPARα^FL/FL mice were randomized to receive 1,3 butanediol (1,3-BDO), a precursor of BHOB, in drinking water for 6 weeks. 1,3-BDO treatment resulted in a significant increase in plasma BHOB levels, a significant decrease in mean arterial blood pressure, improvement in systolic and diastolic function, a decrease in vascular stiffness, and improved exercise performance in PPARα^HEPKO mice. 1,3-BDO treatment did not alleviate hepatic steatosis in PPARα^HEPKO mice; however, it improved plasma cholesterol levels and decreased cardiac lipid accumulation, fibrosis, and apoptosis. 1,3-BDO treatment also resulted in a significant increase in cardiac AMP-activated protein kinase (AMPK) levels. Increasing plasma BHOB levels reverses CVD in our mouse model of MASLD. A similar approach could be an effective strategy for preventing the development of CVD in patients with human MASLD.