Background
In human failing hearts (HF) of different origin (coronary artery disease-CAD, dilated-DCM, restrictive and hypertrophic cardiomyopathy-OTHER), we investigated the active forms of Ca2+/calmodulin-dependent protein kinase IIδ (p-Thr287-CaMKIIδ, oxMet281/282-CaMKIIδ) and their role in phenotypes of the disease.
Conclusion
This is the first demonstration that the posttranslational activation of CaMKIIδ differs in HF depending on etiology. Lower levels of downstream molecular targets of CaMKIIδ do not correlate with either activation of CaMKIIδ or the expression of major protein phosphatases in the HF. Thus, it is unlikely that these mechanisms exclusively underlie failing of the heart.
Results
Although basic diagnostic and clinical markers indicating the attenuated cardiac contractility and remodeling were comparable in HF groups, CaMKIIδ-mediated axis was different. P-Thr287-CaMKIIδ was unaltered in CAD group, whereas it was upregulated in non-ischemic cardiomyopathic groups. No correlation between the upregulated p-Thr287-CaMKIIδ and QT interval prolongation was detected. Unlike in DCM, oxMet281/282-CaMKIIδ did not differ among HF groups. Independently of CaMKIIδ phosphorylation/oxidation, activation of its downstreams-phospholamban and cardiac myosin binding protein-C was significantly downregulated supporting both diminished cardiac lusitropy and inotropy in all hearts. Content of sarcoplasmic reticulum Ca2+-ATPase 2a in all HF was unchanged. Protein phosphatase1β was upregulated in CAD and DCM only, while 2A did not differ among groups.