Calcium/calmodulin Dependent Protein Kinase II Chronic Activation Participates in Hyperglycemia-Induced Diabetic Complications and Heart Failure
Calcium/calmodulin dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain. Chronic activation of the enzyme can, however, produce pathology such as arrhythmias and heart failure and in signaling pathways involving ion channels, calcium handling, and gene transcription. Overactivation of the enzyme is induced by diabetic hyperglycemia and is considered a key risk factor in diabetes for heart disease and neurodegeneration.It has been reported in a new paper that cardiomyocytes (heart cells) exposed to glucose levels corresponding to borderline diabetic to severe diabetic hyperglycemia (240–500 mg/dl) have robust activation of CaMKII.
The authors summarize: “Overactivation of CaMKII caused by hyperglycaemia during diabetes may lead to widespread and as yet unappreciated pathological consequences that merit exploration. It is already known that overactivation of CaMKII occurs in heart failure and neuronal excitotoxicity, and that this activated CaMKII can contribute to major dysfunction at the level of acute ion channel modulation that contributes to cardiac arrhythmias, reduced contractility, neuronal damage, and altered gene transcription. In diabetes, these powerful CaMKII signalling pathways are likely to be activated by hyperglycaemia-induced O-GlcNAc modification of CaMKII and this should be considered in future therapeutic strategies. This could also broaden the impact of CaMKII inhibitors in therapeutics in heart disease and beyond.” (emphasis added)
Curcumin Is an Inhibitor of CaMKII
Just last year, a paper was published reporting that curcumin is an inhibitor of CaMKII in vitro. In that paper, the authors also pointed to important functions of CaMKII in learning and memory (via its effects on long term potentiation) and in pathological glutamate signalling. In fact, the enzyme is highly expressed in the forebrain and is, amazingly, said to comprise 2 percent of the total protein in the hippocampus!
The authors cite studies of curcuminoids (curcumin and related analogs found in turmeric root) showing that curcumin decreases the corticosterone-induced elevated phosphorylation (activation) of CaMKII. They also explain: “Thus pyrazole-curcumin [a synthetic derivative of curcumin studied by the researchers] as well as natural curcumin could offer neuroprotective action in the excitotoxic [glutamate pathway] cascade by inhibiting CaMKII activity.”
So here we have a newly revealed mechanism of hyperglycemia-induced diabetic complications as well as a natural product that may be a suitable therapy for overactivation of the enzyme involved in the induction of these complications. These protective effects of curcumin and curcuminoids expand the list of already impressive potential benefits from taking these compounds at a level, which might be ingested by people eating traditional Indian (Asian) diets high in turmeric root. We enjoy Indian food but take a regular turmeric root supplement because Sandy doesn’t have the time to cook elaborate Indian recipes very often.
HAPPY NEW YEAR!!
- Erickson et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature. 502:372-6 (2013).
- Mayadevi et al. Curcumin is an inhibitor of calcium/calmodulin dependent protein kinase II. Bioorg Med Chem. 20:6040-7 (2012).