Formoterol fumarate attenuates atherosclerosis and improves cardiometabolic dysfunction in ApoE-deficient mice

Apolipoprotein E-deficient (ApoE KO) mice develop severe dyslipidemia, atherosclerosis, vascular dysfunction, and hepatic metabolic abnormalities, closely mimicking human cardiometabolic disease. Formoterol fumarate (FF), a long-acting β₂-adrenergic receptor agonist, has been implicated in metabolic regulation; however, its potential novel effects on atherosclerosis-associated multi-organ dysfunction have not been thoroughly characterized.

Eight-week-old male ApoE KO mice received FF of two doses (0.1 and 0.3 mg/kg/day) or vehicle for 8 weeks. Body weight, serum lipid profiles, and liver and heart damage biomarkers were measured. En face Oil Red O staining and aortic root histopathology assessed atherosclerotic lesion load. Plaque macrophage infiltration was assessed by CD68 immunofluorescence. Isolated aortic ring testing measured vascular reactivity. Cine MRI studied cardiac structure and function. MRI-derived PDFF and R2* mapping were used to assess hepatic fat content and tissue characteristics, respectively. Levels of lipid and collagen in the liver were evaluated.

FF treatment significantly reduced serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol in a dose-dependent manner, accompanied by a marked reduction in atherosclerotic plaque burden and CD68-positive macrophage accumulation within plaques. FF dose-dependently improved vascular reactivity by enhancing endothelium-dependent relaxation without affecting endothelium-independent responses. Cardiac MRI demonstrated the FF improved left ventricular systolic function, characterized by reduced end-diastolic and end-systolic volumes and increased ejection fraction, stroke volume, and cardiac output, without changes in heart rate or left ventricular mass. In addition, FF alleviated hepatic lipid deposition and fibrosis, reduced serum aminotransferase levels, and significantly decreased hepatic lipid accumulation as demonstrated by reduced PDFF and R2* values on MRI.

FF confers broad cardiometabolic protection in ApoE KO mice, characterized by lipid lowering, attenuation of atherosclerosis, improvement of vascular and cardiac function, and amelioration of hepatic metabolic abnormalities and fibrosis. These findings provide new evidence for FF as a potential therapeutic candidate for cardiometabolic disease associated with dyslipidemia.