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Role of mitochondrial reactive oxygen species and actin polymerization in PKC‐dependent constriction of small pulmonary but not mesenteric arteries
Author(s) -
Snow Jessica B.,
Sands Michelle A.,
Gonzalez Bosc Laura V.,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.873.15
Subject(s) - hypoxic pulmonary vasoconstriction , protein kinase c , reactive oxygen species , mesenteric arteries , vasoconstriction , chemistry , biophysics , microbiology and biotechnology , biology , medicine , biochemistry , endocrinology , signal transduction , artery
PKC plays a central role in the regulation of vascular smooth muscle (VSM) tone. However, little is known regarding mechanisms by which PKC mediates contraction in pulmonary VSM. We hypothesized that PKCβ elicits pulmonary vasoconstriction through a unique signaling axis involving VSM mitochondrial reactive oxygen species (ROS) and actin polymerization not observed in systemic arteries. The PKC activator phorbol 12‐myristate 13‐acetate (PMA) caused constriction in both endothelium‐disrupted, pressurized rat pulmonary (~150 μm diameter) and mesenteric (~165 μm diameter) arterioles that was independent of an increase in VSM Ca 2+ (measured by fura‐2 fluorescence). Consistent with our hypothesis, the PKCβ inhibitor LY‐333,531 (10 nM), the O 2 − scavenger tiron (10 mM), the mitochondrial‐targeted antioxidant Mito‐CP (0.5 μM), and the actin polymerization inhibitor cytochalasin B (10 μM), blunted reactivity to PMA in pulmonary arteries while having no effect in mesenteric arterioles. Furthermore, PMA increased mitochondrial ROS (measured by Mito‐SOX fluorescence) and caused actin polymerization (measured by Alexa Fluor 488 phalloidin/Alexa Fluor 594 DNase staining) in cultured human pulmonary artery smooth muscle cells. We conclude that PKCβ uniquely enhances mitochondrial ROS production and actin polymerization in the pulmonary circulation to mediate vasoconstriction.