Melanie Modder

Over the last ten years, it has become clear that metabolic pathways involved in cardiovascular health have more regulatory input levels than previously understood. MicroRNAs (miRNAs), which are small non-coding RNA molecules, provide an important example of such a novel layer of regulation. By binding to and inhibiting multiple target messenger RNAs (mRNAs), miRNAs have been shown to be involved in the regulation of practically all biological pathways. In cardiovascular research, one miRNA that has attracted attention for its involvement in metabolic health, is miRNA-33a. This miRNA has been demonstrated to have an important role in the regulation of genes involved in HDL metabolism, cholesterol efflux, fatty acid oxidation, and bile acid synthesis and secretion. In addition, miRNA-33 levels were shown to be increased in cardiovascular disease risk patients. Multiple studies have shown that therapeutic inhibition of miRNA-33a can increase HDL cholesterol levels in mice and monkeys and can attenuate atherosclerosis in mice, by promoting reverse cholesterol transport. However, other studies did not find reduced development of atherosclerosis after miRNA-33a inhibition and studies in miRNA-33a knockout mice show that miRNA-33a deletion induces an obese phenotype with liver steatosis.

We are currently exploring a alternative approach to using miRNA-33a as a target to attenuate atherosclerosis development, which is by using a miRNA-33a-3p mimic. MiRNA-33a-3p is one of the two sub-forms of miRNA-33a (the other being miRNA-33a-5p). Preliminary data shows that, whereas miRNA-33a-5p globally inhibits reverse cholesterol transport and HDL synthesis, miRNA-33a-3p mainly upregulates processes such as lipoprotein lipase (LPL) activity, LDLr mediated uptake, and also very low density lipoprotein (VLDL) production. We hypothesize that by increasing miRNA-33a-3p, instead of lowering miRNA-33a-5p, increased LPL activity and increased LDLr mediated uptake of VLDL remnant particles might lower atherosclerosis development.

My research focusses on the investigation of novel miRNA-based strategies to attenuate atherosclerosis development.