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Articles in PresS, published online ahead of print November 7, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00266.2002
Submitted on April 24, 2002
Accepted on October 31, 2002
1 Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, MI 48202, none
2 Department of Civil Engineering and Geological Sciences, University of Notredam, Southbend, IN, none
* To whom correspondence should be addressed. E-mail: rgupta1{at}hfhs.org.
Although multifunctional Ca2+-calmodulin- dependent protein kinase-II (CaMKII) is known to phosphorylate different proteins in the heart, studies on the status of this enzyme in heart failure (HF) are limited and controversial. The study was performed in left ventricular (LV) myocardium of 6 dogs with HF (left ventricular ejection fraction, 23 ± 2%) produced by multiple sequential intracoronary microembolizations and 6 normal (NL) control dogs. In the homogenate, membrane, and cytosol fractions prepared from LV specimens, CaMKII activity was assayed using CaMKII peptide (281-291) as the substrate by radioactivity assay and its protein level by Western blot. Further, protein level of calmodulin (CaM), which activates CaMKII activity, phosphorylated phospholamban at threonine-17 (PLB-Thr17) and serine-16 (PLB-Ser16), substrates of CaMKII, was determined in LV homogenate by Western blot. In addition, the level of zinc, which inhibits PKM activity, was also determined in LV tissue by inductively coupled plasma mass spectrometry (ICPMS). CaMKII activity was significantly reduced in the homogenate and membrane, but not in the cytosol, of LV myocardium of dogs with HF compared with NL control. Reduced enzyme activity was associated with reduced CaMKII and phosphorylated PLB-Thr17 and PLB-Ser16 levels in LV myocardium of dogs with HF versus NL controls. Further, no significant differences of CaM and zinc levels were observed in LV myocardium between NL and HF dogs. On the basis of these results, we conclude that CaMKII activity is reduced in failing LV myocardium and this abnormality is associated with reduced protein expression level of the enzyme but not due to changes in CaM and zinc levels. Further, we conclude that reduced CaMKII activity and phosphorylated PLB-Thr17 and PLB-Ser16 level may be partly responsible for impaired sarcoplasmic reticulum function in HF.
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