Serum amyloid A (SAA) is predictive of CVD in humans and causes atherosclerosis in mice. SAA has many proatherogenic effects in vitro. However, HDL, the major carrier of SAA in the circulation, masks these effects. The remodeling of HDL by cholesteryl ester transfer protein (CETP) liberates SAA restoring its proinflammatory activity. Here, we investigated whether deficiency of SAA suppresses the previously described proatherogenic effect of CETP. ApoE-/- mice and apoE-/- mice deficient in the three acute-phase isoforms of SAA (SAA1.1, SAA2.1, and SAA3; “apoE-/- SAA-TKO”) with and without adeno-associated virus-mediated expression of CETP were studied. There was no effect of CETP expression or SAA genotype on plasma lipids or inflammatory markers. Atherosclerotic lesion area in the aortic arch of apoE-/- mice was 5.9 ± 1.2%; CETP expression significantly increased atherosclerosis in apoE-/- mice (13.1 ± 2.2%). However, atherosclerotic lesion area in the aortic arch of apoE-/- SAA-TKO mice (5.1 ± 1.1%) was not significantly increased by CETP expression (6.2 ± 0.9%). The increased atherosclerosis in apoE-/- mice expressing CETP was associated with markedly increased SAA immunostaining in aortic root sections. Thus, SAA augments the atherogenic effects of CETP, which suggests that inhibiting CETP may be of particular benefit in patients with high SAA.
|Journal||Journal of Lipid Research|
|State||Published - May 2023|
Bibliographical noteFunding Information:
The studies were supported with resources and facilities provided by the Centers of Biomedical Research Excellence (COBRE) at the University of Kentucky, which was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30 GM127211. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This work was supported by the National Institutes of Health grants HL134731 (to N. R. W. and F. D.) and HL147381 (to L. T. and P. S.), Department of Veterans Affairs BX004275 (to L. T.), Washington University Diabetes Research Center Collaborative Pilot and Feasibility Grant DK020579-42 (to P. S.).
© 2023 THE AUTHORS.
- cholesteryl ester transfer protein
- lipid metabolism
- serum amyloid A
ASJC Scopus subject areas
- Cell Biology