Abstract Th0009: Overexpression of SAA in the liver promotes atherosclerosis in apolipoprotein E-deficient mice lacking SAA1.1, SAA2.1, and SAA3

Objectives: Persistent elevation of acute-phase serum amyloid A (SAA) is characteristic of chronic inflammatory conditions and is associated with increased cardiovascular risk in humans. Murine studies indicate that deficiency of SAA mitigates the development of atherosclerosis. These findings suggest that SAA is not merely a biomarker but also a causal factor in atherogenesis. Using a doxycycline-inducible transgenic system to express SAA in mice, we demonstrate that liver-specific, but not adipocyte-specific, overexpression of SAA1.1 significantly promotes atherosclerosis development in apolipoprotein E-knockout (apoE KO) mice lacking SAA1.1, SAA2.1, and SAA3 (TKE). Approach and Results: Atherosclerotic lipid accumulation was evaluated in 12-week-old male and female apoE KO and TKE mice. These TKE groups included mice harboring a liver-specific, doxycycline-inducible SAA1.1 transgene (TgL-TKE), mice expressing a reverse tet-transactivator in the liver without an SAA gene (TetL-TKE), mice harboring an adipocyte-specific, doxycycline-inducible SAA1.1 transgene (TgF-TKE), and mice expressing a reverse tet-transactivator in adipose tissue without an SAA gene (TetF-TKE). All mice were maintained on a standard rodent diet and euthanized after 8 weeks of receiving drinking water supplemented with doxycycline at a concentration of 1 mg/mL. Plasma lipid levels were measured at 3 weeks, 5 weeks, and at the end of doxycycline treatment, with atherosclerosis quantified at the termination. At the end of the study, plasma SAA, total cholesterol, triglyceride, and non-HDL cholesterol levels were significantly elevated in TgL-TKE male and female mice compared to all other groups. Atherosclerotic lesion area was markedly increased in TgL-TKE male mice (6.2 ± 2.8%) compared to TetL-TKE male mice (0.8 ± 0.2%). Similarly, TgL-TKE female mice exhibited a significantly larger atherosclerotic lesion area (11.7 ± 4.6%) than TetL-TKE female mice (1.0 ± 0.2%). There were no significant differences in atherosclerotic lesion areas between TgF-TKE male mice (0.8 ± 0.27%) and TetF-TKE male mice (2.17 ± 0.71%), or between TgF-TKE female mice (1.25 ± 0.48%) and TetF-TKE female mice (2.34 ± 0.56%). Conclusions: Our findings demonstrate that overexpression of SAA in the liver induces atherosclerosis development, accompanied by a dramatic elevation in non-HDL cholesterol levels in the plasma.