CAMKII in HF Flashcards
Role of CAMKII in HF
The role of CAMKII in HF is one that is less controversial and many findings have supported this. The role of hyperphosphorylation in HF was introduced by Marks et al in 2001 who suggested that that lead to a dissociation of calstabin binding, and increase in open probability of the RyR however, many studies have rebutted this, including one by Valdiva et al 2017 using the same genetic mice and laboratory conditions. Irrespective, hyperphosphorylation is still and important topic.
CAMKII is an important modulator of calcium regulation, and it has various isoforms in the <3, of which its delta format is the most prevalent. When calcium binds to calmodulin, CAMKII is activated, leading to phosphorylation and increased activity
Wehrens et al 2004
They identified using entire site-directed mutagenesis that the binding sites for RyR and CAMKII were totally separate, so no competition.
Zhang et al 2003
In TG mice over-expressing CAMKII they studied the effects of this on the heart. They found that this caused increases in dilated cardiomyopathy, and a 65% reduction in fractional shortening. These mice were also at a risk of premature death.
Upon isolation of the myocytes, there was reduction in the contractility and altered calcium handling
Ai et al 2004
They utilised a rabbit HF model to study the expression of CAMKII. Their study showed, using western blot to quantify protein expression, an increase in expression of CAMKII by about 50-100%. They also demonstrated that by the inhibition of CAMKII in these myocytes, there was a reduction in the Ca leak, which was unaffected by the use of PKA blockers.
Sossalla et al 2010
They then looked at the expression of CAMKII in tissue isolated from diseased human hearts with either dilated or ischemic heart failure. There was increased expression both the nuclear and cytoplasmic variants of CAMKII delta expression, and by the inhibition of CAMKII in these cells, there was a reduction in the Ca2+ sparklet frequency, a reduction in Ca leak, and increase in myocardial contractility
Kreusser et al 2016
Based on this, they identified that CAMKII could be a potential novel therapeutic agent, so wanted to see if it could ‘rescue’ failing heart by cardioprotection.
Earlier work by them had described that CAMKII has two isoforms, a CAMKII d and gamma, which share similar phenotypes, and complete blockade of CAMKII activity is achieved by blocking both of them.
Based on this background, they induced TAC to mice, and then three weeks later they then inhibited both isoforms, in an inducible model type of situation. What their study showed was that by the inhibition of both, even after the MI, there was a prevention of HF possible by altering the remodelling genes. Thus the answer to the question of is CAMKII inhibition following cardiac insult is ‘yes’. There is still a long way to go till this is a novel therapeutic as CAMKII is an important mediator, and there is homology of different CAMKII isoforms, just like PLC, however, this is promising
