Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo.
Signals transduced by the multifunctional calcium/calmodulin-dependent protein kinases (CaMKs), have been suggested to regulate the development of hypertrophy. We address the role of the three multifunctional CaMKs, CaMK I, II, and IV, in this process using transverse aortic constriction (TAC) to induce cardiac hypertrophy in mice. We find a 33% increase in total CaMK activity 7 d after TAC. However, there are no changes in the levels of CaMKI, which is expressed in the ventricles, or CaMKIV, which is not detectable in the ventricles. Moreover, mice null for the CaMKIV gene develop ventricular hypertrophy and induce the expression of selected hypertrophy marker mRNAs, indicating that CaMKIV is not required at any time during the development of hypertrophy. On the other hand, TAC does increase both mRNA and protein levels of specific isoforms of CaMKII derived from both gamma and delta genes. Included among these isoforms are those that localize to both cytoplasm and nucleus. Collectively, the increased levels of CaMKII isoforms result in a constitutive increase in the Ca(2+)/calmodulin-independent activity of CaMKII in the ventricles. We conclude that CaMKII is the multifunctional CaMK most likely to mediate Ca(2+)- dependent protein phosphorylation events in response to TAC-induced cardiac hypertrophy.
Colomer
Josep M
JM
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Mao
Lan
L
Rockman
Howard A
HA
Means
Anthony R
AR
D000818:Animals; D001011:Aorta; D001794:Blood Pressure; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology; D003250:Constriction; D004195:Disease Models, Animal; D054736:Elongation Factor 2 Kinase; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
D007527:Isoenzymes; D012333:RNA, Messenger; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517598:Camk1 protein, mouse; C517685:Camk4 protein, mouse; C517681:Pnck protein, mouse; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase