Our research program is focused on examining electrophysiological processes in the cardiovascular system, with emphasis on K⁺ channels and their role in regulating cardiac excitability in health and disease. We hope to provide a better understanding of the complex molecular diversity of ion channels in the cardiovascular system and add to our understanding of the relationships between the structure and function of channel proteins in health and disease. Current work focuses on the following projects:

Sarcolemmal K_ATP channels in the cardiovascular system: Cardiac K_ATP channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice which express dominant negative Kir6.x pore-forming subunits (Kir6.1-AAA or Kir6.2-AAA) in cardiac myocytes by driving their expression with the aplha-myosin heavy chain promoter. Weight gain and development after birth of these mice were similar to non-transgenic mice, but an increased mortality was noted after the age of 4-5 months. Transgenic mice lacked cardiac K_ATP channel activity as assessed with patch clamp techniques. Consistent with a decreased current density observed at positive voltages, the action potential duration was increased in these mice. Some myocytes developed early afterdepolarizations following isoproterenol treatment. Hemodynamic measurements revealed no significant effects on ventricular function (apart from a slightly elevated heart rate) whereas in-vivo electrophysiological recordings revealed a prolonged ventricular effective refractory period in transgenic mice. The transgenic mice tolerated stress less well as evident from treadmill stress tests. The pro-arrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggests that these features are intrinsic to the myocardium and that K_ATP channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations. Using Cre-lox technology, we developed additional transgenic models in which Kir6.x dominant negative subunits are expressed tissue-specifically. By targeting K_ATP channels specifically in the endothelium or smooth muscle, we are uncovering interesting and unexpected roles for these channels in the regulation of the coronary blood flow.

Large-scale profiling of the ion channel transcriptome in development and disease: The recent development of efficient tools for large-scale analysis of gene expression has provided new insights into the involvement of gene networks and regulatory pathways in various processes. A popular method is the use of DNA microarrays. Real-time quantitative RT-PCR is a promising alternative for molecular ion channel profiling, being far more precise, reproducible and quantitative. The assay is more useful for analyzing weakly expressed genes, such as ion channel genes. We developed a large-scale real-time RT-PCR assay to assay the expression profiles of over 300 ion channel genes in the heart and vasculature. Current projects involve the examination of ion channel transcriptional alterations occurring in several diseases, including hypertension and diabetes. We recently completed a study in which we examined ion channel expression of over 200 ion channel genes in the heart during perinatal development. This technique is also currently being used to examine how ion channels are altered by fetal programming induced by maternal obesity.