The Role of Ion Channels in Protection

Cardiovascular Ion Channels and Their Role in Protection

PKC epsilon in a cardiac myocyte

Our research involves a multi-disciplinary approach to the study of cardiovascular ion channels and their role in the physiological processes underlying protection. Our major interests focus on ATP and voltage-sensitive potassium channels. The role of ion channels in cardioprotection has been controversial, but ground breaking research at the University of Leicester has begun to elucidate novel signalling mechanisms modulating channel function, and has recently identified a previously uncharacterised cardiac ion channel. Using a wide range of techniques, our group studies channel function from the level of ion channel subunit expression right up to the effects of channels on whole vessel and whole heart function.

 

Examples of current and recent projects

Adult cardiac myocytes are notoriously difficult to transfect. We have developed successful strategies to overcome this problem using both lipid-based and viral methods. We have also established methods for culturing, transfecting and recording ionic currents from cultured smooth muscle cells. These technologies give us the tools to investigate the fundamental role of ion channels in the biology of these key cardiovascular cell types.

Dr Dave Lodwick, Dr Nina Storey and Dr Richard Rainbow have developed an adenoviral delivery system for RNA interference and are using the approach to investigate the role of ATP-sensitive potassium channel subunit isoforms in ischaemic preconditioning, in collaboration with Dr Nina Storey. We have also developed luciferase-based methods for evaluating shRNA efficiency in cultured cells. Using adenoviral shRNA constructs, we have identified a novel ATP-sensitive potassium channel in the heart that is the focus of a BHF project grant held by Dr Richard Rainbow.

Ventricular myocytes

The effects of extracellular glucose on cardioprotection has been a key area of research for the group led by Dr Richard Rainbow. Their work has demonstrated that the protection afforded to the heart by protective stimuli is abolished with elevated extracellular glucose. These observations correlate well with clinical findings that elevated glucose at the time of heart attack leads to a worse outcome for patients. It is also well established that it is difficult to induce cardioprotection to patients with diabetes. The work of this team has identified a group of signalling molecules, which play a vital role in the modulation of cardiovascular ion channels, that are activated directly by the metabolism of glucose. This activation potentially causes arrhythmias in the heart, additional contraction of blood vessels and so may explain the worsened outcome for patients with high glucose. Inhibition of these signalling molecules completely reverses these negative effects of glucose and restores cardioprotection.

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