Nuclear Calcium/Calmodulin-dependent Protein Kinase II Signaling Enhances Cardiac Progenitor Cell Survival and Cardiac Lineage Commitment.
Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) signaling in the heart regulates cardiomyocyte contractility and growth in response to elevated intracellular Ca(2+). The δB isoform of CaMKII is the predominant nuclear splice variant in the adult heart and regulates cardiomyocyte hypertrophic gene expression by signaling to the histone deacetylase HDAC4. However, the role of CaMKIIδ in cardiac progenitor cells (CPCs) has not been previously explored. During post-natal growth endogenous CPCs display primarily cytosolic CaMKIIδ, which localizes to the nuclear compartment of CPCs after myocardial infarction injury. CPCs undergoing early differentiation in vitro increase levels of CaMKIIδB in the nuclear compartment where the kinase may contribute to the regulation of CPC commitment. CPCs modified with lentiviral-based constructs to overexpress CaMKIIδB (CPCeδB) have reduced proliferative rate compared with CPCs expressing eGFP alone (CPCe). Additionally, stable expression of CaMKIIδB promotes distinct morphological changes such as increased cell surface area and length of cells compared with CPCe. CPCeδB are resistant to oxidative stress induced by hydrogen peroxide (H2O2) relative to CPCe, whereas knockdown of CaMKIIδB resulted in an up-regulation of cell death and cellular senescence markers compared with scrambled treated controls. Dexamethasone (Dex) treatment increased mRNA and protein expression of cardiomyogenic markers cardiac troponin T and α-smooth muscle actin in CPCeδB compared with CPCe, suggesting increased differentiation. Therefore, CaMKIIδB may serve as a novel modulatory protein to enhance CPC survival and commitment into the cardiac and smooth muscle lineages.
From the Department of Biology, San Diego State University, San Diego, California 92182.
Pearl
P
Quijada
Department of Pharmacology, University of California at Davis, Davis, California 95616, and.
Nirmala
N
Hariharan
From the Department of Biology, San Diego State University, San Diego, California 92182.
Jonathan D
JD
Cubillo
From the Department of Biology, San Diego State University, San Diego, California 92182.
Kristin M
KM
Bala
From the Department of Biology, San Diego State University, San Diego, California 92182.
Jacqueline M
JM
Emathinger
From the Department of Biology, San Diego State University, San Diego, California 92182.
Bingyan J
BJ
Wang
From the Department of Biology, San Diego State University, San Diego, California 92182.
Lucia
L
Ormachea
Department of Pharmacology, University of California at Davis, Davis, California 95616, and.
Donald M
DM
Bers
From the Department of Biology, San Diego State University, San Diego, California 92182.
Mark A
MA
Sussman
From the Department of Biology, San Diego State University, San Diego, California 92182, Cardiovascular Research Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Kingdom of Saudi Arabia cpoizat99@kfshrc.edu.sa.
Coralie
C
Poizat
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D002467:Cell Nucleus / Q000201:enzymology*; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology
D007527:Isoenzymes; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ca2+/calmodulin-dependent protein kinase II (CaMKII); cell death; cell differentiation; histone deacetylase 4 (HDAC4); stem cells