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Nifedipine Inhibits Cardiac Hypertrophy and Left Ventricular Dysfunction in Response to Pressure Overload

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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 Ca2+ channel blocker, inhibits Ca2+ 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.

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Acknowledgment

We thank Daniela Zablocki for critical reading of the manuscript. We also thank Dr. Jeffery D Molkentin for NFAT-Luc mice.

Sources of funding

This work was supported in part by US Public Health Service Grants HL59139, HL67724, HL69020, HL91469, HL67727, HL73048, and AG27211.

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Authors and Affiliations

  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

    Tetsuro Ago, Yanfei Yang, Peiyong Zhai & Junichi Sadoshima

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  1. Tetsuro Ago
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  2. Yanfei Yang
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  3. Peiyong Zhai
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  4. Junichi Sadoshima
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Correspondence to Junichi Sadoshima.

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Tetsuro Ago and Yanfei Yang contributed equally to this work.

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Ago, T., Yang, Y., Zhai, P. et al. Nifedipine Inhibits Cardiac Hypertrophy and Left Ventricular Dysfunction in Response to Pressure Overload. J. of Cardiovasc. Trans. Res. 3, 304–313 (2010). https://doi.org/10.1007/s12265-010-9182-x

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  • DOI: https://doi.org/10.1007/s12265-010-9182-x

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