Current research projects

1. Role of ADMA/DDAH/AGXT2 system in cardiovascular disease

Asymmetric dimethylarginine (ADMA) is an endogenous methylated analogue of L-arginine, which can inhibit all isoforms of nitric oxide synthases. ADMA is derived from the proteolysis of the proteins that are methylated on arginine residues. Elevated levels of ADMA are associated with increased cardiovascular morbidity and mortality, and ADMA has been proposed to be an independent cardiovascular risk factor. Animal and cell culture studies as well as a short-term infusion of ADMA in healthy human volunteers have shown that ADMA can directly cause vascular damage. The major pathway for catabolism of ADMA is to citrulline and methylamines via the enzyme dimethylarginine dimethylaminohydrolase (DDAH). There are two isoforms of DDAH (DDAH1 and DDAH2) in mammals, each encoded by a separate gene. In addition, ADMA can be metabolized through an alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2), which catalyses the transamination of ADMA using either glyoxylate or pyruvate as amino acceptors with formation of asymmetric dimethylguanidinovaleric acid (ADGV). Certain amounts of ADMA are excreted unchanged by kidneys (Figure 1).

Our group is using complementary cell culture and in vivo approaches to determine the role of ADMA/DDAH/AGXT2 system in different manifestations of cardiovascular disease. The cell culture approaches include gene transfer using viral vectors, siRNA-mediated knockdown and CRISPR-CAS9-mediated knockout of the target genes with subsequent evaluation of changes in cell phenotype, proliferation and production of the signaling molecules. In vivo approaches include virus-mediated overexpression, transgenic overexpression and knockout of the genes of interests with subsequent evaluation of the physiological and morphological end points in the animal model of human diseases.

Figure 1. ADMA/DDAH/AGXT2 system and vascular damage

2.    Role of AGXT2/BAIB signaling system in pathogenesis of metabolic syndrome

Alanine-glyoxylate aminotransferase 2 (AGXT2) is a multifunctional mitochondrial aminotransferase that was first identified in 1978. The physiological importance of AGXT2 was largely overlooked for three decades, because AGXT2 is less active in glyoxylate metabolism than is AGXT1, the enzyme that is deficient in primary hyperoxaluria type I. Recently, several novel functions of AGXT2 have been “rediscovered” in the setting of modern genomic and metabolomic studies. It is now apparent that AGXT2 has multiple substrates and products and that altered AGXT2 activity may contribute to the pathogenesis of cardiovascular, renal, neurological and hematological diseases. Our group is specifically interested in studying the role of AGXT2 and its related metabolites in the pathogenesis of atherosclerosis and metabolic syndrome.

3. Role of ADMA/DDAH1 pathway outside of cardiovascular system

We collaborate with other groups on the projects involving the role of ADMA/DDAH1 pathway outside of cardiovascular system. Some diseases and pathological processes, in which this pathway may play an important role, include renal diseases, metabolic diseases, cirrhosis, sepsis, cancer, neurodegenerative diseases and pulmonary diseases.

4. Role of homoarginine in pathogenesis of cardiovascular, renal and metabolic diseases

Homoarginine is an endogenous amino acid, which has been proposed to play a protective role in stroke, heart failure, metabolic syndrome and renal diseases. The exact mechanisms of the proposed protective effects of homoarginine are not entirely understood and are among the research interests of our group.