NO-STRESS · Nitric oxide regulation of repolarisation in the heart: role of mechanical stress

Nitric oxide regulation of repolarisation in the heart: role of mechanical stress

The muscle cells of the heart are called cardiomyocytes. When the heart beats, all the cardiomyocytes contract at the same time, leading to smooth movement of blood through the heart. Cardiomyocyte contraction occurs when electrical impulses trigger an electrical signal in the cardiomyocyte called an action potential. The action potential is the signal to make the cell contract, and is generated by tiny electrical currents flowing through specialised proteins called ion channels. Ion channels open in a specific sequence, and alterations in this sequence can lead to perturbations in the action potential, which can disrupt the synchronous contraction of cardiomyocytes. This is called fibrillation (irregular heart beat). Atrial fibrillation (AF) is the most common arrhythmia, and is a leading risk factor for stroke when blood clots forming in the atria travel to the brain. At the atrial cardiomyocyte level, changes in atrial electrical activity as a result of differences in the expression and function of ion channels are hallmark features of AF. The ion channel Kv1.5 contributes to the length of the action potential (AP), and as such, directly affects action potential duration (APD). Changes in APD occur early in the pathology of AF. Because of its atrial-specific localisation , Kv1.5 may be a target for AF therapies. Another feature of AF is a decrease in the enzyme neuronal nitric oxide synthetase, which produces nitric oxide (NO). There is growing evidence that NO can alter the activity of Kv1.5. This project was conducted to investigate how this regulation occurs in human cardiomyocytes, and whether this is altered in AF, a condition in which NO is depleted. In addition, mechanical regulation of cardiomyocyte electrical activity is receiving increasing attention as contributing factor in various cardiac pathologies where the mechanical environment is altered (including atrial fibrillation). As NO has been shown to be increased by mechanical stress, we wished to investigate whether mechanical regulation of Kv1.5 is altered by NO, as well as investigating the role of the recently characterised mechanically gated ion channel Piezo-1. Increased knowledge in these areas will contribute to our understanding of AF, and may highlight new therapeutic targets. The specific objectives were: i) To investigate the mechanisms underlying the regulation of Kv1.5 by nNOS in human atrial myocytes from patients with and without AF. ii) To understand how mechanical stress is linked to NO production and altered repolarisation in human physiology and AF. iii) Investigate the role of the mechanically activated ion channel Piezo-1 in atrial cardiomyocytes

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