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.