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J Cardiovasc Transl Res. 2010 Aug;3(4):304-13. doi: 10.1007/s12265-010-9182-x. Epub 2010 May 1.

Nifedipine inhibits cardiac hypertrophy and left ventricular dysfunction in response to pressure overload.

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1
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB G-609, Newark, NJ 07103, USA.

Abstract

Pathological hypertrophy is commonly induced by activation of protein kinases phosphorylating class II histone deacetylases (HDACs) and desuppression of transcription factors, such as nuclear factor of activated T cell (NFAT). We hypothesized that nifedipine, an L-type Ca(2+) channel blocker, inhibits Ca(2+) calmodulin-dependent kinase II (CaMKII) and NFAT, thereby inhibiting pathological hypertrophy. Mice were subjected to sham operation or transverse aortic constriction (TAC) for 2 weeks with or without nifedipine (10 mg/kg/day). Nifedipine did not significantly alter blood pressure or the pressure gradient across the TAC. Nifedipine significantly suppressed TAC-induced increases in left ventricular (LV) weight/body weight (BW; 5.09 +/- 0.80 vs. 4.16 +/- 0.29 mg/g, TAC without and with nifedipine, n = 6,6, p < 0.05), myocyte cross-sectional area (1,681 +/- 285 vs. 1,434 +/- 197 arbitrary units, p < 0.05), and expression of fetal-type genes, including atrial natriuretic factor (35. 9 +/- 6.4 vs. 8.6 +/- 3.3 arbitrary units, p < 0.05). TAC-induced increases in lung weight/BW (7.7 +/- 0.9 vs. 5.5 +/- 0.5 mg/g, p < 0.05) and decreases in LV ejection fraction (65.5 +/- 3.1% vs. 75.7 +/- 3.3%, p < 0.05) were attenuated by nifedipine. Nifedipine caused significant inhibition of TAC-induced activation of NFAT-mediated transcription, which was accompanied by suppression of Thr 286 phosphorylation in CaMKII. Nifedipine inhibited activation of CaMKII and NFAT by phenylephrine, accompanied by suppression of Ser 632 phosphorylation and nuclear exit of HDAC4 in cardiac myocytes. These results suggest that a subpressor dose of nifedipine inhibits pathological hypertrophy in the heart by inhibiting activation of CaMKII and NFAT, a signaling mechanism commonly activated in pathological hypertrophy.

PMID:
20559781
PMCID:
PMC3036765
DOI:
10.1007/s12265-010-9182-x
[Indexed for MEDLINE]
Free PMC Article

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