Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides.
BACKGROUND
Although disruption of guanylyl cyclase (GC) A, a natriuretic peptide receptor, induces cardiac hypertrophy and fibrosis, the molecular mechanism underlying these effects are not well understood. In this study, we examined the role of calcineurin, a calcium-dependent phosphatase, in cardiac remodeling in GCA-knockout (GCA-KO) mice.


RESULTS
At 14 weeks of age, calcineurin activity, nuclear translocation of nuclear factor of activated T cells c3 (NFATc3), and modulatory calcineurin-interacting protein 1 (MCIP1) gene expressions were increased in the hearts of GCA-KO mice compared with wild-type (WT) mice. Blockade of calcineurin activation by FK506 (6 mg/kg body weight administered subcutaneously once a day from 10 to 14 weeks of age) significantly decreased the heart-to-body weight ratio, cardiomyocyte size, and collagen volume fraction in GCA-KO mice, whereas FK506 did not affect these parameters in WT mice. Overexpression of atrial and brain natriuretic peptides, collagen, and fibronectin mRNAs in GCA-KO mice was also attenuated by FK506. Electrophoretic mobility shift assays demonstrated that GATA4 DNA-binding activity was increased in GCA-KO mice, and this increase was inhibited by calcineurin blockade. In neonatal cultured cardiac myocytes, inhibition of GCA by HS142-1 (100 microg/mL) increased basal and phenylephrine (10(-6) mol/L)-stimulated calcineurin activity, nuclear translocation of NFATc3, and MCIP1 mRNA expression. In contrast, activation of GCA by atrial natriuretic peptide (10(-6) mol/L) inhibited phenylephrine (10(-6) mol/L)-stimulated nuclear translocation of NFATc3.


CONCLUSIONS
These results suggest that activation of cardiac GCA by locally secreted natriuretic peptides protects the heart from excessive cardiac remodeling by inhibiting the calcineurin-NFAT pathway.
Tokudome
Takeshi
T
Department of Biochemistry, Research Institute, National Cardiovascular Center, Suita, Osaka, Japan.
Horio
Takeshi
T
Kishimoto
Ichiro
I
Soeki
Takeshi
T
Mori
Kenji
K
Kawano
Yuhei
Y
Kohno
Masakazu
M
Garbers
David L
DL
Nakao
Kazuwa
K
Kangawa
Kenji
K
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D006332:Cardiomegaly / Q000209:etiology* / Q000473:pathology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005355:Fibrosis / Q000209:etiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000172:deficiency* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C494008:NFATC3 protein, human; C108612:RCAN1 protein, human; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D016559:Tacrolimus