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Cardiac Overexpression of Adenylyl Cyclase Type 5 Induces Left Ventricular Hypertrophy Potentially by Activating Calcineurin‐NFAT Signaling
Author(s) -
Park Misun,
Park Ji Yeon,
Lee Jung Ah,
Tian Bin,
Lai Lo,
Iwatsubo Kosaku,
Ishikawa Yoshihiro,
Sadoshima Junichi,
Vatner Dorothy E.,
Vatner Stephen F.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.365.11
Adenylyl cyclase types 5 and 6 (AC5 and AC6) are the major cardiac AC isoforms, but appear to regulate responses to pressure overload differently, e.g. protein levels of AC5 increase whereas AC6 decrease. Even at baseline left ventricular (LV) hypertrophy (H) was observed in AC5‐transgenic mice (TG), i.e. myocyte cross sectional area increased (572±31μm 2 ) compared to either WT (339±12μm 2 ) or AC6‐TG (300±14 μm 2 ). To understand the mechanism, we examined microarray‐based gene expression analysis of both AC5‐TG and AC6‐TG at baseline, and compared these data with a public dataset of pressure overload LVH in wild type (WT) mice. We found several up‐regulated genes associated with LVH in AC5‐TG, e.g., Nppb, Postn, Fn1, Ctgf. One of the major mediators of LVH is the calcineurin‐NFAT pathway. Based on transcription factor binding sites analysis, we found a significant enrichment for NFAT binding sites in up‐regulated genes in AC5‐TG (p<0.001). We confirmed the translocation of NFAT to the nucleus in AC5‐TG hearts by immunohistochemical staining. Gene density heat map analysis also showed the correlation of gene expression profiles between AC5‐TG and public dataset of calcineurin‐TG. The protein expression of calcineurin was increased 1.3 fold in AC5‐TG. In summary, LVH is present at baseline without superimposed stress in AC5‐TG, but not AC6‐TG mice, potentially involving the calcineurin‐NFAT signaling pathway.