Myeloid Cell–Specific ATP-Binding Cassette Transporter A1 Deletion Has Minimal Impact on Atherogenesis in Atherogenic Diet–Fed Low-Density Lipoprotein Receptor Knockout Mice

• DOI: 10.1161/atvbaha.114.303791
• Publication Date: 2014-05-16T07:33:15Z
• Authors: Xin Bi; Xuewei Zhu; Chuan Gao; Swapnil Shewale; Qiang Cao; Mingxia Liu; Elena Boudyguina; Abraham K. Gebre; Martha D. Wilson; Amanda L. Brown; John S. Parks
• Keywords: Male; Mice, Knockout; Genotype; Cholesterol, VLDL; Cholesterol, LDL; Atherosclerosis; Mice, Inbred C57BL; Mice; Cholesterol; Receptors, LDL; Macrophages, Peritoneal; Animals; Diet, Atherogenic; Female; Myeloid Cells; Aorta; Triglycerides; ATP Binding Cassette Transporter 1; Bone Marrow Transplantation

Objective— Transplantation studies suggest that bone marrow cell ATP-binding cassette transporter A1 protects against atherosclerosis development. However, the in vivo effect of macrophage ATP-binding cassette transporter A1 expression on atherogenesis is not fully understood because bone marrow contains other leukocytes and hematopoietic stem and progenitor cells. Myeloid-specific ATP-binding cassette transporter A1 knockout mice in the low-density lipoprotein (LDL) receptor knockout C57BL/6 background were developed to address this question.

Approach and Results— Chow-fed myeloid-specific ATP-binding cassette transporter A1 knockout/LDL receptor knockout (double knockout [DKO]) versus LDL receptor knockout (single knockout [SKO]) mice had similar plasma lipid concentrations, but atherogenic diet (AD)–fed DKO mice had reduced plasma very-LDL (VLDL)/LDL concentrations resulting from decreased hepatic VLDL triglyceride secretion. Resident peritoneal macrophages from AD-fed DKO versus SKO mice had significantly higher cholesterol content but similar proinflammatory gene expression. Atherosclerosis extent was similar between genotypes after 10 to 16 weeks of AD but increased modestly in DKO mice by 24 weeks of AD. Lesional macrophage content was similar, likely because of the higher monocyte flux through aortic root lesions in DKO versus SKO mice. After transplantation of DKO or SKO bone marrow into SKO mice and 16 weeks of AD feeding, atherosclerosis extent was similar and plasma apolipoprotein B lipoproteins were reduced in mice receiving DKO bone marrow. When differences in plasma VLDL/LDL concentrations were minimized by maintaining mice on chow for 24 weeks, DKO mice had modest, but significantly more, atherosclerosis compared with SKO mice.

Conclusions— Myeloid cell ATP-binding cassette transporter A1 increases hepatic VLDL triglyceride secretion and plasma VLDL/LDL concentrations in AD-fed LDL receptor knockout mice, offsetting its atheroprotective role in decreasing macrophage cholesterol content, resulting in a minimal increase in atherosclerosis.