Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK

Journal Article · Mon Nov 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.08.010· OSTI ID:21460236

Sandhu, Hardip ^[1]; Xu, Cang Bao ^[2]; Edvinsson, Lars ^[1]

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1. Department of Clinical Experimental Research, Glostrup Research Institute, Ndr. Ringvej 69, 2600 Glostrup (Denmark)
2. Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, University Hospital of Lund, Lund (Sweden)

Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET{sub B}) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-{kappa}B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-{kappa}B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET{sub B} receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET{sub B} receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET{sub B} receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET{sub B} receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET{sub B} receptors. Thus, the MAPK-mediated upregulation of contractile ET{sub B} receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke.

• OSTI ID: 21460236
• Journal Information: Toxicology and Applied Pharmacology, Vol. 249, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.08.010; PII: S0041-008X(10)00283-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACTINOMYCIN
CEREBRAL ARTERIES
CYCLOHEXIMIDE
LIPIDS
RATS
RECEPTORS
TOBACCO SMOKES
VASCULAR DISEASES
AEROSOLS
ANIMALS
ANTIBIOTICS
ANTI-INFECTIVE AGENTS
ANTIMITOTIC DRUGS
ANTINEOPLASTIC DRUGS
ARTERIES
BLOOD VESSELS
BODY
CARDIOVASCULAR SYSTEM
COLLOIDS
DISEASES
DISPERSIONS
DRUGS
FUNGICIDES
MAMMALS
MEMBRANE PROTEINS
ORGANIC COMPOUNDS
ORGANS
PESTICIDES
PROTEINS
RESIDUES
RODENTS
SMOKES
SOLS
VERTEBRATES