Peroxisome proliferator-activated receptor gamma coactivator 1 alpha protects cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 signaling pathway

摘要

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a crucial coregulator interacting with multiple transcriptional factors in the regulation of cardiac hypertrophy. The present study revealed that PGC-1 alpha protected cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 (NFATc4) signaling pathway. Overexpression of PGC-1 alpha by adenovirus infection prevented the increased protein and messenger RNA expression of NFATc4 in phenylephrine (PE)-treated hypertrophic cardiomyocytes, whereas knockdown of PGC-1 alpha by RNA silencing augmented the expression of NFATc4. An interaction between PGC-1 alpha and NFATc4 was observed in both the cytoplasm and nucleus of neonatal rat cardiomyocytes. Adenovirus PGC-1 alpha prevented the nuclear import of NFATc4 and increased its phosphorylation level of NFATc4, probably through repressing the expression and activity of calcineurin and interfering with the interaction between calcineurin and NFATc4. On the contrary, PGC-1 alpha silencing aggravated PE-induced calcineurin activation, NFATc4 dephosphorylation, and nuclear translocation. Moreover, the binding activity and transcription activity of NFATc4 to DNA promoter of brain natriuretic peptide were abrogated by PGC-1 alpha overexpression but were enhanced by PGC-1 alpha knockdown. The effect of PGC-1 alpha on suppressing the calcinuerin-NFATc4 signaling pathway might at least partially contribute to the protective effect of PGC-1 alpha on cardiomyocyte hypertrophy. These findings provide novel insights into the role of PGC-1 alpha in regulation of cardiac hypertrophy.