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Project 5: A light-inducible Na+ pump to understand the role of intracellular Na+ accumulation in heart failure

PI Göttingen: T. Brügmann; PI London: M.J. Shattock; PhD student: Svenja M. Kiehn

 

Scientific background and preliminary results

Heart failure is the inability of the heart to supply oxygenated blood to the organs, tissues and cells caused by pathological stress leading to cardiac remodeling with altered structure, changes in electrophysiological behavior and diminished pump function of the heart. One major aspect of pathological cardiac remodeling is intracellular sodium (Na_i) accumulation. Under physiological conditions, Na_i varies between 4-8 mM but in heart failure, (HF) Na_i can be elevated up to 200%. This elevated Na_i is presumed to be a key player in cardiac hypertrophy and heart failure as it can trigger 1) the increase of reactive oxygen species in mitochondria, which can lead to energy deficiency 2) change the transport rates of sodium-calcium exchanger (NCX) and sodium-potassium ATPase (NKA) and hence, influence the excitation contraction coupling and 3) reverse the NCX which can mediate calcium release of the sarcoplasmic reticulum (SR). Importantly, only the NKA carries sodium in significant amounts out of the cell and unfortunately, so far, its transport rate could not be increased pharmacologically and thus the question remains whether the failing heart could be in principle be treated by decreasing Na_i?

Optogenetics is a new approach to affect the physiology of cells by expressing light-activated proteins and illumination. In 2010, the light-gated non-selective cation channel channelrhodopsin-2 was used in the heart. The induction of an action potential - both in vitro using cardiomyocytes (CM) and in vivo using transgenic mouse hearts - by illumination with blue light could be reported.  Additional studies showed the termination of atrial fibrillation and ventricular arrhythmia using light-induced de- and hyperpolarization. Within this project we will develop and evaluate a new optogenetic approach to decrease Na_i with light and decipher the therapeutical potential of this mechanism in general.