After an insult, a series of stress events are activated in the heart leading to heart failure. To prevent processes leading to adverse cardiac remodeling, cardiomyocytes activates gene expression pathways which closely resemble to those observed in fetal cardiac development. One of such cascade activated is Notch signaling pathway which plays a critical role during mammalian cardiac development. Notch is an evolutionarily conserved signaling pathway that is important for multiple cellular processes, including cell fate determination, differentiation, proliferation, apoptosis, and regeneration during embryonic and early postnatal development. Activation of this signaling pathway involves the interaction of membrane bound Notch receptor with Delta-like or/Jagged ligand. Following this interaction, protease complex γ-secretase cleaves the notch intracellular domain (NICD) which translocates to the nucleus and promotes gene expression of hairy and enhancer of split (HES) and hairy transcription factor (HRT) by binding to the protein suppressor RBP-J. This notch transduction system is gradually silenced in the heart after birth but is partly restored in myocardium following injury.
On the contrary, expression of voltage-gated K channels is progressively increased during postnatal development, leading to the acquisition of the mature electrical phenotype. These outward Kcurrents are critical determinant of the action potential (AP) profile of the cardiomyocytes. Importantly, K channels are reduced after myocardial infarction, an event that is accompanied by reactivation of Notch signaling. At this year’s AHA scientific sessions, I presented my work on hypothesis that NICD transduction system contributes to the electrical remodeling of myocytes of the diseased heart.
Our electrophysiological studies in NICD-GFP transgenic mice showed that activation of NICD presents a prolongation of early repolarization phase of AP which is primarily determined by the outward Kv currents. Upon further investigation, voltage clamp experiments displayed significant decrease in various components of Kv currents in myocytes expressing NICD compared to control. To establish a causative link between notch activation and electrophysiological properties of myocytes under pathological conditions, we induced the myocardial infarction in C57Bl/6 WT mice and perturbed the notch signaling in these mice by using an antagonist of γ-secretase. Isolated cardiomyocytes from these mice prevented the reduction of Kv currents compared to the myocytes from non-treated mice where Kv currents are substantially reduced. Taken together my poster summarized that Notch signaling is an important regulator of the electrical properties of cardiomyocytes under normal and pathological conditions.
Presenting my work at AHA was one of the biggest highlights at the conference. Not only I got the opportunity to share my research with such a large audience, I was elated to receive positive input regarding my work from the experts whose papers I have read. This trip has definitely connected me with greater scientific community and opened doors for potential collaborations. I have returned home feeling energetic and inspired. I can’t wait to be back at AHA 2018.
Keerat Kaur is a postdoctoral fellow at Icahn school of Medicine at Mount Sinai in department of cardiology, NY. Her research focuses on reprogramming non-cardiacmyocytes to cardiomyocytes using modified mRNA approach.