Calcium channel blockers ameliorate iron overload-associated hepatic fibrosis by altering iron transport and stellate cell apoptosis.
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.
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Department of Pathology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Disease, Shijiazhuang 050200, Hebei, People's Republic of China.
Ying
Y
Zhang
Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei, People's Republic of China.
Xin
X
Zhao
Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, People's Republic of China.
Yanzhong
Y
Chang
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Yuanyuan
Y
Zhang
Department of Pharmacy, The Forth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, People's Republic of China.
Xi
X
Chu
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Xuan
X
Zhang
Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Zhenyi
Z
Liu
Department of Medicinal Chemistry, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Hui
H
Guo
Department of Physiology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Na
N
Wang
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China.
Yonggang
Y
Gao
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China. Electronic address: zhangjianping14@126.com.
Jianping
J
Zhang
Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang 050200, Hebei, People's Republic of China; Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Shijiazhuang 050200, Hebei, People's Republic of China. Electronic address: chuli0614@126.com.
Li
L
Chu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology / Q000627:therapeutic use; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use
D002121:Calcium Channel Blockers; C576839:TIMP1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D009553:Nimodipine; D003094:Collagen; D014700:Verapamil; D007501:Iron; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D004110:Diltiazem; D003676:Deferoxamine
Apoptosis; Calcium channel blockers; Fibrosis; Hepatic stellate cells; Iron overload; Transmembrane transport