Narine Sarvazyan Laboratory
ONGOING PROJECTS
ORIGINS OF ECTOPIC BEATS. Our lab is investigating how macroscopic ectopic beats are formed. Our in vitro experiments suggest that these beats occur during a so-called Ectopic Nexus state. The latter refers to a functional state of an injured cardiac tissue in which multiple poorly-coupled ectopic sources form a transient "wave breeding" microenvironment. In this microenvironment, ectopic activity develops from the firing of individual cells to slowly propagating local intercellular waves (Arutunyan et al 2001,2002, 2003). These local waves are confined to the area of injury, but can spread to normal tissue upon change in external conditions. We have characterized the parameter space in which generation of local waves takes place and described, both numerically and experimentally, how the system behaves under dynamic conditions (Pumir at al 2005, Biktashev et al 2008). Currently, we are exploring dual metabolic and optical mapping approach to investigate generation of ectopic beats in situ (Swift et al 2008, Kay et al 2008).
N-CADHERIN-MEDIATED STEM CELL ADHESION. We developed a new mouse embryonic stem cell line that constitutively overexpresses N-cadherin. The latter is a major adhesion protein found in the intercalated discs. We have shown that overexpression of N-cadherin leads to marked changes in the phenotype and adhesion of these cells, both during embryoid body formation and cell differentiation stages. We hypothesize that overexpressing N-cadherin would allow transplanted stem cells to integrate more efficiently to a host myocardium, and that increased adhesion would facilitate gap junctional connections between the host and graft cells. Indeed, in vitro, N-cadherin overexpressing cells showed elevated levels of p120, a protein involved in N-cadherin trafficking and stabilization. They also markedly overexpressed connexin-43, a gap junction protein that facilitates intercellular communication (Karabekian et al 2009). Our next step is to conduct in vivo testing, in order to determine if N-cadherin overexpression improves the ability of stem cell derived-cardiomyocytes to engraft.
ADVERSE EFFECTS OF PLASTICIZERS ON CARDIAC FUNCTION. The growing number of parents, scientists and health advocates are raising concerns about wide use of plasticizers such as phthalates. As of today the majority of studies have focused on adverse effects of phthalates on reproductive health and their role in cancer. In contrast, the cardiac effects of DEHP remained largely understudied. This made our recent experimental findings particularly intriguing. Specifically, when we applied clinically relevant concentrations of DEHP to monolayers of rat neonatal cardiomyocytes, we discovered that it markedly decreases the conduction velocity, diminishes the amount of connexin-43 and impairs cell adhesion (Gillum et al 2009). DEHP treatment has also disrupted expression of a large number of genes, pointing to pathways contributing to an arrhythmogenic phenotype (Posnack et al 2011). Our next step is to explore how DEHP can affect cardiac function in vivo.