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Mitochondria control NF‐κB‐dependent functional Ca V 1.2 expression in cerebral artery smooth muscle cells
Author(s) -
Narayanan Damodaran,
Xi Qi,
Pfeffer Lawrence,
Jaggar Jonathan
Publication year - 2010
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.24.1_supplement.603.7
Subject(s) - depolarization , thapsigargin , myocyte , chemistry , medicine , endocrinology , biology , microbiology and biotechnology , endoplasmic reticulum
In myocytes of resistance‐size cerebral arteries, we investigated Ca 2+ signals that regulate mitochondrial Ca 2+ concentration ([Ca 2+ ] mito ) and tested the hypothesis that [Ca 2+ ] mito controls ion channel transcription, thereby regulating contractility. Endothelin‐1 (ET‐1), a vasoconstrictor, activated Ca 2+ waves, elevated global intracellular Ca 2+ concentration ([Ca 2+ ] i ), elevated [Ca 2+ ] mito , caused mitochondrial depolarization, and stimulated ROS generation in arterial myocytes. Thapsigargin, a sarcoplasmic reticulum (SR) Ca 2+ ATPase inhibitor and xestospongin C (XeC), an IP 3 receptor (IP 3 R) inhibitor, blocked ET‐1‐induced [Ca 2+ ] mito elevation, mitochondrial depolarization, and ROS elevation. ET‐1 stimulated the generation of mitochondria‐derived ROS which subsequently stimulated an additional small rise in NAD(P)H oxidase‐derived ROS. ET‐1‐induced IP 3 R‐mediated mitochondrial ROS stimulated nuclear translocation of the NF‐κB p50 subunit and NF‐κB‐dependent luciferase activity. NF‐κB p105 knockdown reduced basal Ca V 1.2 channel expression and attenuated pressure (myogenic tone)‐ and depolarization‐induced, Ca V 1.2 channel‐dependent vasoconstriction. ET‐1 elevated Ca V 1.2 channel expression, myogenic tone, and depolarization‐induced vasoconstriction, and these effects were blocked by XeC, bortezomib, a proteasome inhibitor, and NF‐κB p105 knockdown. These data indicate that in arterial myocytes, IP 3 R‐mediated SR Ca 2+ release controls [Ca 2+ ] mito , which regulates mitochondrial ROS generation. Mitochondrial ROS regulate NF‐κB activity, which controls functional Ca V 1.2 channel expression. Thus, myocyte mitochondria control arterial contractility by regulating NF‐κB‐dependent functional Ca V 1.2 channel expression. AHA GSE 09PRE2220266, NIH R01077678.