Laboratory of Cardiovascular Genomics

Dimitris Kardassis, PhD

Atherosclerotic Cardiovascular Disease (ASCVD) is the leading cause of death worldwide. Several risk factors including obesity, type II diabetes, non-alcoholic fatty liver disease, and dyslipidemia predispose to ASCVD by mechanisms that are not fully understood. Reliable genetic or non-genetic biomarkers are also needed in order to increase the value of current risk prediction algorithms. In our lab, we are studying the genetic determinants of atherosclerosis using animal models combined with virus-mediated gene transfer and omics technologies with the goal to understand better the pathogenesis of atherosclerosis and to identify novel biomarkers and drug targets for ASCVD.

1. Mechanisms that control the transcription of key genes of HDL metabolism

We have been studying the mechanisms that control the transcription of the human apolipoprotein genes (the protein components of lipoproteins) since 1990 and we have pioneered the elucidation of the roles of hormone nuclear receptors such as HNF-4 and LXRs in human lipoprotein metabolism. During the past decade we have focused our attention on the regulation of genes involved in High Density Lipoprotein (HDL) metabolism...

Regulation of the human apoM gene by hormone nuclear receptors, HNF-1, and Jun proteins in hepatic cells. From: Mosialou et al. (2010) J Biol Chem. 285(40):30719-30; Mosialou et al (2011) J Biol Chem. 286(19):17259-69

The gene encoding the membrane transporter ABCA1 is essential for HDL biogenesis. Mutations in the ABCA1 gene cause Tangier’s disease which is characterized by the absence of HDL particles and premature atherosclerosis...

Proposed mechanism of transcriptional repression of the gene encoding the lipid transporter ABCA1 in hepatic cells by the transcription factor FOXA2 (HNF-3β). From Thymiakou and Kardassis (2014) Biochim Biophys Acta Gene Regul Mech. 1839(6):526-36

We studied the regulation of the human lipoprotein lipase (LPL) gene which is essential for the hydrolysis of triglycerides (TG) from TG-rich lipoproteins. Mutations in LPL gene cause hypertriglyceridemia and acute pancreatitis...

Proposed mechanism of transcriptional regulation of the gene encoding human lipoprotein lipase (LPL). From Kanaki et al. (2016) Atherosclerosis 255:34-43

2. Identification of gene signatures associated with the progression of the metabolic syndrome in mice before and after treatment with RYGB surgery

The metabolic syndrome (MetS) is a cluster of clinical disorders such as dyslipidemia, diabetes, and obesity which are associated with increased risk for cardiovascular disease...

Differential gene expression analysis comparing HFD vs LFD groups of apoE3L.CETP mice at different time points (4, 8, and 12 weeks). (A) Venn diagram (B) Heatmap. From: Nasias et al. (2019) J Cell Physiol. 234(11):20485-20500

3. Utilization of animal models combined with adenovirus-mediated gene transfer to functionally characterize mutations in genes of HDL metabolism

In our lab, we have used adenovirus-mediated gene transfer and transgenic technology to study the effects of mutations in proteins of HDL metabolism on HDL structure and functions in vivo...

Diet-induced atherosclerosis in transgenic mice expressing WT or mutant forms of human apoA-I. From: Tiniakou et al. (2015) Atherosclerosis 243(1):77-85

4. Genetics Studies

We identified by next-generation sequencing and characterized exonic single nucleotide polymorphisms (SNPs) in 10 genes of HDL metabolism in a Greek cohort with extreme HDL cholesterol levels...

A. 3D ribbon representation of ApoA-IV. From: Chroni et al. (2020) Arch Biochem Biophys. 696:108655

5. The Atheroprotective Mechanisms of HDL and How They Are Compromised in Chronic Inflammation

HDL has numerous atheroprotective functions which are facilitated by the interaction of apoA-I with cell surface receptors such as SR-BI or ABCA1 in HDL target cells...

ApoA-I deficiency in mice results in a more severe phenotype of Antigen-Induced Arthritis. From: Tiniakou et al (2015) J Immunol. 194(10): 4676-87

Proposed mechanism for the regulation of the expression of the human ANGPTL4 gene by HDL in endothelial cells. From: Theofilatos et al. (2018) Metabolism. 87:36-47