Oxidized CaMKII: a "heart stopper" for the sinus node?

Abstract

Each normal heart beat is triggered by an electrical impulse emitted from a group of specialized cardiomyocytes that together form the sinoatrial node (SAN). In this issue of the JCI, Swaminathan and colleagues demonstrate a new molecular mechanism that can disrupt the normal beating of the heart: angiotensin II - typically found in increased levels in heart failure and hypertension - oxidizes and activates Ca2+/calmodulin-dependent kinase II via NADPH oxidase activation, causing SAN cell death. The loss of SAN cells produces an electrical imbalance termed the "source-sink mismatch," which may contribute to the SAN dysfunction that affects millions of people later in life and complicates a number of heart diseases.

Figure 1. Mechanism of Ang II–induced SND.

Normally, the small volume of excited tissue in the SAN (source) depolarizes the neighboring quiescent atrial tissue (sink). In conditions with increased Ang II, NADPH oxidase is activated, leading to oxidation of two methionine residues of CaMKII, rendering the enzyme autonomously active. Elevated activity of CaMKII leads to SAN cell death, reducing the threshold volume of automatic cells of the SAN and increasing non-excitable tissue in the form of fibrosis. This increased electrotonic loading produces a source-sink mismatch (explained in detail in the text), slows the beating rate, and causes SND. CT, crista terminalis; IAS, inferior atrial septum.