Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice

Abstract

Guidelines to reduce cardiovascular risk in diabetes include aggressive LDL lowering, but benefits are attenuated compared with those in patients without diabetes. Consistent with this, we have reported in mice that hyperglycemia impaired atherosclerosis regression. Aldose reductase (AR) is thought to contribute to clinical complications of diabetes by directing glucose into pathways producing inflammatory metabolites. Mice have low levels of AR, thus raising them to human levels would be a more clinically relevant model to study changes in diabetes under atherosclerosis regression conditions. Donor aortae from Western diet-fed mice were transplanted into normolipidemic wild-type, Ins2Akita ( , insulin deficient), human AR (hAR) transgenic, or /hAR mice. mice had impaired plaque regression as measured by changes in plaque size and the contents of CD68 cells (macrophages), lipids, and collagen. Supporting synergy between hyperglycemia and hAR were the even more pronounced changes in these parameters in /hAR mice, which had atherosclerosis progression in spite of normolipidemia. Plaque CD68 cells from the /hAR mice had increased oxidant stress and expression of inflammation-associated genes but decreased expression of anti-inflammatory genes. In summary, hAR expression amplifies impaired atherosclerosis regression in diabetic mice, likely by interfering with the expected reduction in plaque macrophage inflammation.

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice

“…iNOS staining was performed on formalin-fixed tissue and permeabilized using 0.05% Tween and 1% Triton X-100, followed by incubation with a conjugated iNOS antibody (Abcam, Ab209027) incubated overnight at 4°C. Collagen content was determined by Picrosirius Red (Abcam) staining as previously done (41). A Hamatsu NanoZoomer 2.0 was used to obtain images of NETs and iNOS staining; a Leica SP 5 Confocal Microscope was used to obtain images of NLRP3 and caspase-1 staining.…”

RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in macrophage inflammation and cholesterol metabolism

“…In atherosclerosis regression, prominent roles for macrophage dysfunction have been uncovered through fate mapping, fluorescent bead labeling of monocytes/macrophages, single-cell and bulk RNA-sequencing, and using genetically modified animals and pharmacological treatments (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Roles for impaired emigration of macrophages from established plaques to skewed inflammatory processes, in which overabundance of pro-versus antiinflammatory macrophage gene expression impairs regression, particularly in diabetes, have been uncovered (4,19).…”

Aldose Reductase: An Emerging Target for Development of Interventions for Diabetic Cardiovascular Complications

“…Murine studies, in atherosclerosis regression models, attributed the impairment to hyperglycemia-induced monocytosis and recruitment of these macrophages to plaques (181). Yuan et al (182), using Type 1 diabetic Akita mice with and without hAR overexpression and aortic transplantation model, addressed the role of AR in impaired atherosclerosis regression in diabetes. In the surgical model of atherosclerosis regression, the donor aortic arch containing the preformed atherosclerotic plaques are transplanted into a recipient mice that are kept on normal chow diet.…”