Dr Amelia Power from the Department of Physiology and her colleagues from the University of Otago recently published their research understanding the signalling pathways that lead to cardiac arrythmias in the top cardiovascular research journal Circulation Research. The article is titled “Nitric Oxide Modulates Ca2+ Leak and Arrhythmias via S-Nitrosylation of CaMKII”.
When the heart is stimulated to work harder, such as during the flight-or-fight response, calcium calmodulin dependent kinase II (CaMKII) is activated which results in phosphorylation and activation of downstream calcium handling proteins which are responsible for the coordinated release of calcium which triggers each heartbeat. CaMKII can be modulated by several post-translational modifications which mostly cause chronic activation of CaMKII which leads to pathological conditions such as arrhythmia and heart failure.
Nitric oxide has been known to modulate cardiac arrythmias both negatively and positively, yet the mechanism remained controversial. Their publication demonstrates that two cysteine residues on CaMKII (C273 and C290) are targets for S-nitrosylation by nitric oxide yet have opposing effects. They used genetically modified mouse models that lacked the nitrosylation sites to demonstrate that S-nitrosylation at the C273 site provided a break on CaMKII and protected the against arrythmias in the whole heart and arrythmogenic calcium waves in isolated cardiomyocytes. While the C290 nitrosylation site is involved in prolonging CaMKII activity and promotes arrythmias, acting like an accelerator. Given nitric oxide is produced endogenously within cardiomyocytes during the flight-or-response and can be administered clinically their research supports growing evidence for the inhibition of CaMKII as a therapy for cardiac arrhythmias.
This publication reflects years of work and a collaborative effort with authors from five different universities across New Zealand and the USA.
Link to the paper