Identification of dysregulation of atrial proteins in rats with chronic obstructive apnea using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry.

Obstructive sleep apnea (OSA) affects an estimated 20% of adults worldwide and has been associated with electrical and structural abnormalities of the atria, although the molecular mechanisms are not well understood. Here, we used two-dimensional polyacrylamide gel electrophoresis (2D PAGE) coupled with nanoliquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) to investigate the proteins that are dysregulated in the atria from severe and moderate apnea when compared to control. We found enzymes involved in the glycolysis, beta-oxidation, electron transport chain and Krebs cycle to be down-regulated.

Atrial electrophysiological and molecular remodelling induced by obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) affects 9-24% of the adult population. OSA is associated with atrial disease, including atrial enlargement, fibrosis and arrhythmias. Despite the link between OSA and cardiac disease, the molecular changes in the heart which occur with OSA remain elusive.

Functional consequences of Kir2.1/Kir2.2 subunit heteromerization.

Kir2 subunits form channels that underlie classical strongly inwardly rectifying potassium currents. While homomeric Kir2 channels display a number of distinct and physiologically important properties, the functional properties of heteromeric Kir2 assemblies, as well as the stoichiometries and the arrangements of Kir2 subunits in native channels, remain largely unknown. Therefore, we have implemented a concatemeric approach, whereby all four cloned Kir2 subunits were linked in tandem, in order to study the effects of Kir2.

Heterogeneity of IK1 in the mouse heart.

Previous studies have shown that cardiac inward rectifier potassium current (I(K1)) channels are heteromers of distinct Kir2 subunits and suggested that species- and tissue-dependent expression of these subunits may underlie variability of I(K1). In this study, we investigated the contribution of the slowly activating Kir2.3 subunit and free intracellular polyamines (PAs) to variability of I(K1) in the mouse heart.

Transgenic upregulation of IK1 in the mouse heart is proarrhythmic.

The role of the cardiac current Ik1 in arrhythmogenesis remains highly controversal. To gain further insights into the mechanisms of IK1 involvement in cardiac excitability, we studied the susceptibility of transgenic mice with altered IK1 to arrhythmia during various pharmacological and physiological challenges. Arrhythmogenesis was studied in transgenic mice expressing either dominant negative Kir2.

Cardiac IK1 underlies early action potential shortening during hypoxia in the mouse heart.

It is established that prolonged hypoxia leads to activation of K(ATP) channels and action potential (AP) shortening, but the mechanisms behind the early phase of metabolic stress remain controversial. Under normal conditions IK1 channels are constitutively active while K(ATP) channels are closed. Therefore, early changes in IK1 may underlie early AP shortening.

Transgenic overexpression of SUR1 in the heart suppresses sarcolemmal K(ATP).

The lack of pathological consequences of cardiac ATP-sensitive potassium channel (K(ATP)) channel gene manipulation is in stark contrast to the effect of similar perturbations in the pancreatic beta-cell. Because the pancreatic and cardiac channel share the same pore-forming subunit (Kir6.2), the different effects of genetic manipulation likely reflect, at least in part, the tissue-specific expression of the regulatory subunit (SUR1 in pancreas vs.

Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability.

To assess the functional significance of upregulation of the cardiac current (IK1), we have produced and characterized the first transgenic (TG) mouse model of IK1 upregulation. To increase IK1 density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel was expressed in the heart under control of the alpha-myosin heavy chain promoter.

Dominant-negative suppression of I(K1) in the mouse heart leads to altered cardiac excitability.

The inward rectifier potassium current in the heart, I(K1), has been suggested to play a significant role in cardiac excitability by contributing to the late phase of action potential (AP) repolarization and the stabilization of resting potential. To further assess the role of I(K1) in cardiac excitability we have produced transgenic mice expressing a dominant-negative subunit of the Kir2.1 channel, a major molecular determinant of I(K1) in the heart, and studied the effects of I(K1) suppression on major potassium currents, APs and the overall electrical activity of the heart.