Heart-specific deletion of CnB1 reveals multiple mechanisms whereby calcineurin regulates cardiac growth and function.
Calcineurin is a protein phosphatase that is uniquely regulated by sustained increases in intracellular Ca(2+) following signal transduction events. Calcineurin controls cellular proliferation, differentiation, apoptosis, and inducible gene expression following stress and neuroendocrine stimulation. In the adult heart, calcineurin regulates hypertrophic growth of cardiomyocytes in response to pathologic insults that are associated with altered Ca(2+) handling. Here we determined that calcineurin signaling is directly linked to the proper control of cardiac contractility, rhythm, and the expression of Ca(2+)-handling genes in the heart. Our approach involved a cardiomyocyte-specific deletion using a CnB1-LoxP-targeted allele in mice and three different cardiac-expressing Cre alleles/transgenes. Deletion of calcineurin with the Nkx2.5-Cre knock-in allele resulted in lethality at 1 day after birth due to altered right ventricular morphogenesis, reduced ventricular trabeculation, septal defects, and valvular overgrowth. Slightly later deletion of calcineurin with the alpha-myosin heavy chain Cre transgene resulted in lethality in early mid adulthood that was characterized by substantial reductions in cardiac contractility, severe arrhythmia, and reduced myocyte content in the heart. Young calcineurin heart-deleted mice died suddenly after pressure overload stimulation or neuroendocrine agonist infusion, and telemetric monitoring of older mice showed arrhythmia leading to sudden death. Mechanistically, loss of calcineurin reduced expression of key Ca(2+)-handling genes that likely lead to arrhythmia and reduced contractility. Loss of calcineurin also directly impacted cellular proliferation in the postnatal developing heart. These results reveal multiple mechanisms whereby calcineurin regulates cardiac development and myocyte contractility.
Maillet
Marjorie
M
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio 45229-3039, USA.
Davis
Jennifer
J
Auger-Messier
Mannix
M
York
Allen
A
Osinska
Hanna
H
Piquereau
Jérôme
J
Lorenz
John N
JN
Robbins
Jeffrey
J
Ventura-Clapier
Renée
R
Molkentin
Jeffery D
JD
D000818:Animals; D001145:Arrhythmias, Cardiac; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002118:Calcium; D049109:Cell Proliferation; D017353:Gene Deletion; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D021122:Protein Subunits
D021122:Protein Subunits; D019703:Calcineurin; D002118:Calcium