Abstract Body: Introduction: Cardiovascular diseases cause more morbidity and mortality globally than any other disease. One of the major risk factors for cardiovascular atherosclerotic disease is hypercholesterolemia due to higher plasma cholesterol in apolipoprotein B-containing lipoproteins. Available therapeutic approaches mainly depend on inhibiting cholesterol absorption by the gut and enhanced clearance of these lipoproteins by the liver using ezetimibe and statins, respectively. Our approach focuses on utilizing microRNAs (miRNAs) to treat hyperlipidemia. miRNAs interact with different mRNAs, reducing protein translation and affecting numerous biological pathways simultaneously for favorable physiological outcomes. We have recently shown that the miRNA-30c analog C2 reduces plasma cholesterol and apoB-containing lipoproteins by inhibiting hepatic lipoprotein assembly and secretion without obvious side effects in mice, monkeys and human hepatocytes by decreasing lipoprotein assembly and secretion.
Hypothesis: Since C2’s mode of action is distinct from statins and ezetimibe, we hypothesized that C2 would work with these drugs to reduce cholesterol beyond what is achievable with individual therapeutics in Apoe^−/− mice.
Methods: Western diet fed female Apoe^−/− mice were divided into four groups (n=9/group). They were treated with PBS, C2, statin + ezetimibe (SE), or C2+statin+ezetimibe (CSE) for one month.
Results: Our data show that SE and C2 individually lower plasma cholesterol and apoB in IDL/LDL fractions compared to PBS treated control mice. More importantly, a combination of SE and C2 reduced cholesterol and apoB-lipoprotein levels more than individual treatments. Similar additive reductions in atherosclerotic plaque areas, lipid deposition and macrophage levels were observed in the CSE (combination) group compared to the other three groups. These increased reductions were not associated with increases in the liver injury and inflammatory markers.
Conclusions: Therefore, a combination therapy of statin, ezetimibe and C2 is likely to be more efficacious in reducing plasma cholesterol and apoB levels, as well as atherosclerotic lesions.