Mitochondria Control Functional CaV1.2 Expression in Smooth Muscle Cells of Cerebral Arteries

Circ Res. 2010 Sep 3;107(5):631-41. doi: 10.1161/CIRCRESAHA.110.224345. Epub 2010 Jul 8.

Abstract

Rationale: Physiological functions of mitochondria in contractile arterial myocytes are poorly understood. Mitochondria can uptake calcium (Ca(2+)), but intracellular Ca(2+) signals that regulate mitochondrial Ca(2+) concentration ([Ca(2+)](mito)) and physiological functions of changes in [Ca(2+)](mito) in arterial myocytes are unclear.

Objective: To identify Ca(2+) signals that regulate [Ca(2+)](mito), examine the significance of changes in [Ca(2+)](mito), and test the hypothesis that [Ca(2+)](mito) controls functional ion channel transcription in myocytes of resistance-size cerebral arteries.

Methods and results: Endothelin (ET)-1 activated Ca(2+) waves and elevated global Ca(2+) concentration ([Ca(2+)](i)) via inositol 1,4,5-trisphosphate receptor (IP(3)R) activation. IP(3)R-mediated sarcoplasmic reticulum (SR) Ca(2+) release increased [Ca(2+)](mito) and induced mitochondrial depolarization, which stimulated mitochondrial reactive oxygen species (mitoROS) generation that elevated cytosolic ROS. In contrast, a global [Ca(2+)](i) elevation did not alter [Ca(2+)](mito), mitochondrial potential, or mitoROS generation. ET-1 stimulated nuclear translocation of nuclear factor (NF)-kappaB p50 subunit and ET-1-induced IP(3)R-mediated mitoROS elevated NF-kappaB-dependent transcriptional activity. ET-1 elevated voltage-dependent Ca(2+) (Ca(V)1.2) channel expression, leading to an increase in both pressure (myogenic tone)- and depolarization-induced vasoconstriction. Baseline Ca(V)1.2 expression and the ET-1-induced elevation in Ca(V)1.2 expression were both reduced by IP(3)R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF-kappaB subunit knockdown, leading to vasodilation.

Conclusions: IP(3)R-mediated SR Ca(2+) release elevates [Ca(2+)](mito), which induces mitoROS generation. MitoROS activate NF-kappaB, which stimulates Ca(V)1.2 channel transcription. Thus, mitochondria sense IP(3)R-mediated SR Ca(2+) release to control NF-kappaB-dependent Ca(V)1.2 channel expression in arterial myocytes, thereby modulating arterial contractility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Calcium / metabolism*
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling* / drug effects
  • Cerebral Arteries / metabolism
  • Endothelin-1 / metabolism
  • Homeostasis
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Luminescent Proteins / biosynthesis
  • Luminescent Proteins / genetics
  • Male
  • Membrane Potential, Mitochondrial
  • Microscopy, Confocal
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Sarcoplasmic Reticulum / metabolism
  • Time Factors
  • Transcriptional Activation
  • Transfection
  • Uncoupling Agents / pharmacology
  • Vasoconstriction* / drug effects

Substances

  • Antioxidants
  • Cacna1c protein, rat
  • Calcium Channels, L-Type
  • Endothelin-1
  • Inositol 1,4,5-Trisphosphate Receptors
  • Luminescent Proteins
  • NF-kappa B
  • Reactive Oxygen Species
  • Uncoupling Agents
  • Calcium