Mutation of a single cysteine in CaMKIIδ protects the heart from ischemia-reperfusion Injury

Abstract CaMKIIδ is the dominant isozyme of Ca2+/calmodulin-dependent protein kinase II in the heart. Under certain pathological conditions, it can be oxidized, causing a constitutive activation that can lead to cardiac failure. We recently showed that, in purified CaMKIIδ exposed to oxidative conditions, a disulfide link formed between Cys273 and Cys290 causes this autonomous activation. Cys273 has a low pKa that facilitates the oxidation of its thiol to a sulfenic acid at physiological pH. Does this matter in vivo? To answer that question, we created a transgenic mouse with Cys273 mutated to serine (CaMKIIδC273S) to prevent disulfide formation. We conducted a detailed assessment of cardiac function at rest and in a dobutamine stress test. We found that the CaMKIIδ Cys273Ser mutation does not have deleterious effects on cardiac physiology. Then, we assessed whether the mutation would protect the heart from ischemia-reperfusion in the Langendorff model. The CaMKIIδC273S mouse had improved cardiac function and decreased infarct size compared to the wild-type mouse. We conclude that blocking disulfide formation at Cys273 protects the heart against ischemia-reperfusion injury. Drugs that specifically target Cys 273 may be therapeutic in human cardiac disease. Competing Interest Statement The authors have declared no competing interest.