Skip to main content
eScholarship
Open Access Publications from the University of California

UCLA

UCLA Electronic Theses and Dissertations bannerUCLA

Non-pharmacological Strategies to Suppress Triggers of Cardiac Arrhythmias by Targeting L-Type Ca2+ Channels

Abstract

Sudden cardiac death is one of the major leading causes of death in the United States, affecting about 300,000 people annually on average. Cardiac arrhythmias and ventricular fibrillation can be triggered, at the cellular level, by the presence of aberrations of the cardiac action potential (AP) known as early afterdepolarizations (EADs). EADs are single or multiple voltage oscillations largely induced by the reactivation of L-type Ca2+ currents (ICa,L) during phase 2 and phase 3 of a cardiac AP. Our recent studies using dynamic clamp techniques have suggested that EADs and their arrhythmogenic consequences can be potently suppressed by subtle reduction the ICa,L current non-inactivating (pedestal) component and/or minimal changes (3-5 mV) in the voltage dependence of activation. Exploiting the modulatory effects of L-type Ca2+ channel (LTCC) auxiliary β2 subunits on the non-inactivating component of ICa,L, we sought to investigate the effects of knocking down Cavβ2 subunit expression levels in rabbit ventricular myocytes in the presence of an oxidative stress known to trigger EADs (H2O2). We hypothesized that reducing the expression level of endogenous Cavβ2 decreases the probability of EAD occurrence in cardiomyocytes exposed to H2O2. Using an adenoviral infection to deliver a short hairpin RNA (shRNA) specific for targeting Cavβ2 that inhibits its gene expression by binding to its mRNA transcripts, our results showed that myocytes expressing less Cavβ2 mRNA exhibited no EADs; whereas, the control myocytes infected with GFP alone as a control group were more susceptible to EAD occurrence in 0.6 mM H2O2. These results suggest that Cavβ2 could be a potential target for gene therapy and could give insights to other therapeutic strategies that could possibly be implemented.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View