Abstract 6252: Altered Expression of Cardiac-Specific MicroRNAs in the Hearts of Mice with Combined Diabetes and Atherosclerosis
Diabetes may not only serve as a major risk factor for atherosclerosis but also can substantially accelerate cardiac injury triggered by atherosclerosis. Recently certain microRNA species have been reported to be potentially novel biomarkers, modulators and therapeutic targets for cardiovascular disease. This study established a new murine model with a combination of diabetes and atherosclerosis to investigate the roles of microRNA in regulation of target gene expression in the hearts. Apolipoprotein E-null (ApoE−/−) mice were induced to develop diabetes by injection of multiple low doses of streptozotocin (STZ). Following STZ injection for one week or more, significantly increased blood glucose levels were found in STZ treated ApoE−/−mice by 2.8 ± 0.3 folds vs. ApoE−/− alone (p<0.01), whereas STZ injection did not alter circulating inflammatory marker C-reactive protein (0.01 mg/ml), cholesterol and LDL cholesterol. Analysis of microRNAs by use of the mirVana qRT-PCR miRNA detection assay revealed that ApoE−/− mice with STZ injection had increased cardiac levels of microRNAs, miR-208 by 2.8 ± 0.5 folds, miR-133 by 3.6 ± 0.6 folds, and miR-1 by 3.1 ± 0.4 folds (p<0.05). The ApoE−/− mice with STZ injection also showed increased levels of β-myosin heavy chain (βMHC) but reduced expression of the cardiac potassium channels (HERG, KCNE1 and KCNQ1) and insulin-like growth factor 1 (IGF-1). Because βMHC serves as the target of miR-208, HERG/ KCNQ1 as the targets of miR-133, and KCNE1 and IGF-1 as the targets of miR-1, the changes in expression of these molecules may reflect the microRNA functional alternation during the development of diabetes in atherosclerosis. Thus, the development of diabetes in atherosclerosis-prone mice is characterized by increased cardiac specific microRNA expression, which is associated with up-regulation of the hypertrophy marker βMHC and down-regulation of the cardiac functional factors including potassium channels and growth factors. These data suggest that expression of microRNA species induced by combined diabetes/atherosclerosis factors may precipitate the outcome of cardiac function by regulating cardiac gene expression, and therefore are the useful biomarkers for cardiac dysfunction in atherosclerosis.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).