Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis

Journal Article · Wed Jun 15 00:00:00 EDT 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.04.008· OSTI ID:22689187

Zhang, Ying ^[1]; Zhao, Xin ^[2]; Chang, Yanzhong ^[3]; Zhang, Yuanyuan ^[1]; Chu, Xi ^[4]; Zhang, Xuan ^[1]; Liu, Zhenyi; Guo, Hui ^[5]; Wang, Na ^[6]; Gao, Yonggang ^[1]; Zhang, Jianping ^[1]; Chu, Li ^[1]

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1. Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China)
2. Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei (China)
3. Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei (China)
4. Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei (China)
5. Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China)
6. Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei (China)

Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n = 8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth. - Highlights: • Calcium channel blockers (CCBs) reduced hepatic iron content. • CCBs decreased hepatic fibrotic areas and collagen expression levels. • CCBs resolve fibrosis by regulating iron transport and inhibiting HSC growth.

• OSTI ID: 22689187
• Journal Information: Toxicology and Applied Pharmacology, Vol. 301; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ABSORPTION
ABSORPTION SPECTROSCOPY
ANIMAL TISSUES
APOPTOSIS
ATOMIZATION
CALCIUM
COLLAGEN
DEFEROXAMINE
DISEASE INCIDENCE
DMSO
DOSES
DRUGS
ELECTRIC POTENTIAL
FERRITIN
FIBROSIS
HYDROXYPROLINE
IN VITRO
IRON
LIVER
MICE
MOLECULAR BIOLOGY
RECEPTORS
SULFATES
TRANSFERRIN
TRANSMISSION ELECTRON MICROSCOPY
TRANSPORT