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 Ldlr−/− mice were transplanted into normolipidemic wild-type, Ins2Akita (Akita+/−, insulin deficient), human AR (hAR) transgenic, or Akita+/−/hAR mice. Akita+/− 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 Akita+/−/hAR mice, which had atherosclerosis progression in spite of normolipidemia. Plaque CD68+ cells from the Akita+/−/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.