Plasma membrane Ca2+-ATPase isoform 4 antagonizes cardiac hypertrophy in association with calcineurin inhibition in rodents.
How Ca2+-dependent signaling effectors are regulated in cardiomyocytes, given the extreme cytoplasmic Ca2+ concentration changes that underlie contraction, remains unknown. Cardiomyocyte plasma membrane Ca2+-ATPase (PMCA) extrudes Ca2+ but has little effect on excitation-contraction coupling, suggesting its potential role in controlling Ca2+-dependent signaling effectors such as calcineurin. We generated cardiac-specific inducible PMCA4b transgenic mice that displayed normal global Ca2+ transient and cellular contraction levels and reduced cardiac hypertrophy following transverse aortic constriction (TAC) or phenylephrine/Ang II infusion, but showed no reduction in exercise-induced hypertrophy. Transgenic mice were protected from decompensation and fibrosis following long-term TAC. The PMCA4b transgene reduced the hypertrophic augmentation associated with transient receptor potential canonical 3 channel overexpression, but not that associated with activated calcineurin. Furthermore, Pmca4 gene-targeted mice showed increased cardiac hypertrophy and heart failure events after TAC. Physical associations between PMCA4b and calcineurin were enhanced by TAC and by agonist stimulation of cultured neonatal cardiomyocytes. PMCA4b reduced calcineurin nuclear factor of activated T cell-luciferase activity after TAC and in cultured neonatal cardiomyocytes after agonist stimulation. PMCA4b overexpression inhibited cultured cardiomyocyte hypertrophy following agonist stimulation, but much less so in a Ca2+ pumping-deficient PMCA4b mutant. Thus, Pmca4b likely reduces the local Ca2+ signals involved in reactive cardiomyocyte hypertrophy via calcineurin regulation.
Wu
Xu
X
Department of Pediatrics, Division of Molecular Cardiovascular Biology, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Chang
Baojun
B
Blair
N Scott
NS
Sargent
Michelle
M
York
Allen J
AJ
Robbins
Jeffrey
J
Shull
Gary E
GE
Molkentin
Jeffery D
JD
D000818:Animals; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D065095:Calcineurin Inhibitors; D050778:NFATC Transcription Factors; D011994:Recombinant Proteins; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases