Intracellular zinc status influences cisplatin-induced endothelial permeability through modulation of PKCα, NF-κB and ICAM-1 expression.
Platinum-based chemotherapeutic regimen induces vascular dysfunction. Action of cisplatin on endothelial cells is mediated by protein kinase C (PKC-α), which further activates nuclear factor-κB (NF-κB) and induces canonical transient receptor potential channel (TRPC1) and intercellular adhesion molecule (ICAM-1) expression. Increased ICAM-1 contributes to hyperadhesion of monocytes and endothelial dysfunction. PKC-α is also involved in phosphorylation of TRPC1, resulting in store-operated calcium entry (SOCE) and further activation of NF-κB. Although the role of altered intracellular zinc status is not known in cisplatin-induced vascular dysfunction, because of the ability of zinc to modulate PKC-α, NF-κB activity, we hypothesized that zinc can ameliorate the extent of endothelial dysfunction induced by cisplatin. Human umbilical vein endothelial cells treated with cisplatin (8.0μg/ml) showed lowered intracellular free zinc, concomitant with enhanced activation of PKC-α, NF-κΒ activation, TRPC1, SOCE and ICAM-1 levels. Zinc deficiency per se induced using membrane permeable chelator (TPEN) mimicked the cisplatin-induced PKC-α, NF-κB activation and ICAM-1 expression, but also activated Activator Protein-1 (AP-1). Zinc supplementation (2.0-10.0μM) to the endothelial cells during cisplatin treatment or TPEN-induced zinc deficiency suppressed PKC-α, NF-κB, TRPC1, SOCE activation and lowered the ICAM-1 expression. Zinc supplementation thereby effectively decreased the cisplatin-induced endothelial permeability and adherence of the activated endothelial cells to U937 monocytes.
Department of Molecular Biology, Institute of Genetics & Hospital for Genetic Diseases, Begumpet, Osmania University, Hyderabad 500016, Telangana, India.
Vijaya Lakshmi
VL
Bodiga
Department of Molecular Biology, Institute of Genetics & Hospital for Genetic Diseases, Begumpet, Osmania University, Hyderabad 500016, Telangana, India.
Santhi Priya
SP
Inapurapu
Department of Biotechnology, KL University, Vaddeswaram 522502, Andhra Pradesh, India.
Praveen Kumar
PK
Vemuri
Department of Biochemistry, Kakatiya University, Warangal 506009, Telangana, India.
Madhukar Rao
MR
Kudle
Department of Biochemistry, Kakatiya University, Warangal 506009, Telangana, India. Electronic address: sbodiga@gmail.com.
Sreedhar
S
Bodiga
D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050052:TRPC Cation Channels / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
D016328:NF-kappa B; D050052:TRPC Cation Channels; D018808:Transcription Factor AP-1; C096351:transient receptor potential cation channel, subfamily C, member 1; D018799:Intercellular Adhesion Molecule-1; D051571:Protein Kinase C-alpha; D015032:Zinc; D002945:Cisplatin; D002118:Calcium
Cisplatin; ICAM-1; NF-κB; PKC; SOCE; TRPC1; Zinc