title: Nifedipine inhibits cardiac hypertrophy and left ventricular dysfunction in response to pressure overload.
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.
authors.affiliation: 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.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Yang
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000465:Algorithms; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000187:drug effects / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013318:Stroke Volume; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control*
chemical_list: D002121:Calcium Channel Blockers; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D009543:Nifedipine