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Updated: Apr 24, 2026
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Macrophage-derived apoESendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic
Hagai Tavori1, Daping Fan2, Ilaria Giunzioni3
1Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Science University, Portland, OR Section of Cardiovascular Disease Prevention, Division of Cardiovascular Medicine, Departments of Medicine, Vanderbilt University Medical Center, Nashville, TN.
Abstract:
Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoESendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoESendai may also directly influence renal and arterial homeostasis. We investigated the effects of macrophage-expressed apoESendai in apoE(-/-) mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated mice. Macrophage apoESendai expression reduced aortic lesion size and inflammation by 32 and 28%, respectively, compared with apoE2 in apoE(-/-) recipients. No differences in lesion size or inflammation were found between apoESendai and apoE3 in apoE(-/-) recipients. Macrophage apoESendai expression also reduced aortic lesion size by 18% and inflammation by 29% compared with apoE2 in apoE(-/-)/LDLR(-/-) recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE(-/-)/LDLR(-/-) mice expressing apoESendai. Thus, macrophage expression of apoESendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the first demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis.
Insights
The rare apoESendai variant protects arteries from atherosclerosis but causes kidney damage, specifically lipoprotein glomerulopathy (LPG), in mice. This study reveals opposing effects of a single apoprotein on vascular and renal health.
Area of Science:
- Cardiovascular Biology
- Renal Pathophysiology
- Lipid Metabolism
Background:
- Lipoprotein glomerulopathy (LPG) is a kidney disease linked to dyslipidemia and elevated apolipoprotein E (apoE) levels.
- The rare apoESendai (Arg145Pro) mutant, derived from apoE3 but with an apoE2 charge, is known to cause LPG in humans and mice.
- The impact of apoESendai, particularly when expressed by macrophages, on arterial health remained unexplored.
Purpose of the Study:
- To investigate the dual effects of macrophage-expressed apoESendai on both arterial and renal homeostasis.
- To compare the atherogenic and nephritogenic potential of apoESendai with other apoE isoforms (apoE2, apoE3).
- To elucidate the role of the low-density lipoprotein receptor (LDLR) in mediating the effects of macrophage apoESendai.
Main Methods:
- Bone marrow from mice engineered to express apoE2, apoE3, or apoESendai was transplanted into lethally irradiated apoE(-/-) mice, with or without LDLR.
- Atherosclerotic lesion size and macrophage inflammation in the aorta were quantified.
- Renal pathology, including glomerular lesions characteristic of LPG, was assessed in recipient mice.
Main Results:
- Macrophage apoESendai expression significantly reduced aortic lesion size and inflammation compared to apoE2 in apoE(-/-) mice.
- No significant differences in aortic lesions were observed between apoESendai and apoE3 in apoE(-/-) recipients.
- Glomerular lesions indicative of LPG were exclusively found in apoE(-/-)/LDLR(-/-) mice expressing apoESendai, despite its protective effects on atherosclerosis.
Conclusions:
- Macrophage-derived apoESendai exhibits a dual role, conferring protection against atherosclerosis while simultaneously inducing lipoprotein glomerulopathy.
- This study provides the first evidence of an apoprotein variant exerting opposing influences on vascular and renal systems.
- The findings highlight the complex interplay between lipid metabolism, macrophage function, and organ-specific disease pathogenesis.
