Ongoing Research

Atherosclerosis

It is well-known that atherosclerosis occurs in arterial regions of branching points and curves, suggesting a correlation between atherosclerosis and disturbed flow conditions.  However, it was unknown whether disturbed flow is responsible for atherosclerosis. In 2009, my lab directly demonstrated that disturbed blood flow can actually induce atherosclerosis in the presence of additional risk factors such as hypercholesterolemia in ApoE KO mice (Nam 2009 Am J Physiology).

This paper has been a game changer for my own group as this model has enabled us to study the role of disturbed flow from the gene and molecular levels, all the way to the plaque development (something that cannot be done in vitro).  Also, this model has been gaining wide-acceptance in the mechanovascular biology field as one of the most pathophysiologically relevant mouse model of atherosclerosis (cited >165 times). This mouse model, along with another key method of collecting nearly pure endothelial RNAs/DNAs, helped my lab to carry out several genome-wide OMICs-based studies (Ni Blood 2010; Son Nature Comm 2013; Dunn J Clin Invest 2014; Go Am J Physiol 2014; Andueza Cell Reports 2020). These studies have enabled us to discover novel mechanosensitive genes and miRNAs that have been the subject of intense studies in our lab and others.

We identified BMPs from endothelial gene array studies in vitro and have shown that BMP is a pro-inflammatory protein, leading to hypertension and other groups have shown that this causes atherosclerosis. We also showed that the loss of BMP receptor II is caused by pro-atherogenic factors including disturbed flow and that this causes atherosclerosis. Ongoing studies are exploring the mechanisms.

I have been studying signaling pathways by which shear stress regulates G-proteins and protein kinase pathways including MAP kinases, Protein kinase A, PI3K/Akt in endothelial function such as eNOS activation, NADPH oxidation, endothelial inflammation and apoptosis.

Model schema of mouse partial carotid ligation (PCL) surgery.

 

Aortic arch and representative histology images of mouse left and right carotid arteries after partial carotid ligation surgery.

 
 
 

Healthy (left) and diseased (right) aortic valves

Aortic Valve Disease

My lab has been studying the role of shear stress in aortic valve (AV) endothelial biology and AV calcification using both in vitro and ex vivo systems in close collaboration with Ajit Yoganathan at Georgia Tech for more than ten years. Since we showed shear-sensitive transcriptome changes in AV endothelial cells with Jonathan Butcher and Robert Nerem in 2006 (ATVB) and matrix regulating cathepsins with Ajit Yoganathan in 2006 (JHVD), my lab has expanded our lab’s direction to study the shear-sensitive genes by which AV calcification occurs preferentially in the fibrosa side where they are exposed to complex flow conditions. We have now discovered many flow sensitive coding and non-coding (miRNAs) genes and their roles in AV endothelial function and disease.

 

Nanomedicine

Using our mouse partial carotid ligation model and endothelial gene collection methods in vivo, we have been taking additional OMICs approaches such as miR-nome and DNA methylome to understand how flow regulates endothelial biology and atherosclerosis via miRNAs and DNA methylations. We have identified several mechanosensitive miRNAs such as miR-712 and its family member miR-205.  The miR-712 is the first mechanosensitive miRNA that has been shown to play a critical role in atherosclerosis and anti-miR-712 has been shown to prevent atherosclerosis and AAA. More recently, we showed that disturbed flow activates DNMT1, which in turn induces a dramatic DNA-methylome change in endothelial cells, resulting in endothelial inflammation and atherosclerosis.  This paper has opened up new concept that flow can control gene expression and endothelial function by controlling epigenetic programs via DNA methylation. Most recently, we have been expanding our work to nanomedicine by developing a lipid nanoparticles that can be specifically delivered to inflamed arterial endothelium and prevent atherosclerosis (Kherolomoom et al ACS Nano 2015).

3D Multiplexed Imaging

The major goal of this project is to visualize in 3D the expression of flow-sensitive genes and proteins to understand their roles in atherosclerosis and aortic valve disease. In addition, we aim to generate 3D multiomics images for studying atherosclerosis and aortic valve disease by integrating optical clearing and whole-mount multiplexing strategies with multi-scale light-sheet fluorescence microscopy.