Mitochondria Control Functional Ca(V)1.2 Expression in Smooth Muscle Cells of Cerebral Arteries

作者：Narayanan Damodaran; Xi Qi; Pfeffer Lawrence M; Jaggar Jonathan H^*

来源：Circulation Research, 2010, 107(5): 631-U164.

DOI：10.1161/CIRCRESAHA.110.224345

• mitochondria
• calcium signaling
• Ca(V)1.2 expression
• arterial smooth muscle
• myogenic tone

Rationale: Physiological functions of mitochondria in contractile arterial myocytes are poorly understood. Mitochondria can uptake calcium (Ca2+), but intracellular Ca2+ signals that regulate mitochondrial Ca2+ concentration ([Ca2+](mito)) and physiological functions of changes in [Ca2+](mito) in arterial myocytes are unclear.
Objective: To identify Ca2+ signals that regulate [Ca2+] mito, examine the significance of changes in [Ca2+](mito), and test the hypothesis that [Ca2+](mito) controls functional ion channel transcription in myocytes of resistance-size cerebral arteries.
Methods and Results: Endothelin (ET)-1 activated Ca2+ waves and elevated global Ca2+ concentration ([Ca2+](i)) via inositol 1,4,5-trisphosphate receptor (IP3R) activation. IP3R-mediated sarcoplasmic reticulum (SR) Ca2+ release increased [Ca2+](mito) and induced mitochondrial depolarization, which stimulated mitochondrial reactive oxygen species (mitoROS) generation that elevated cytosolic ROS. In contrast, a global [Ca2+] i elevation did not alter [Ca2+] mito, mitochondrial potential, or mitoROS generation. ET-1 stimulated nuclear translocation of nuclear factor (NF)-kappa B p50 subunit and ET-1-induced IP3R-mediated mitoROS elevated NF-kappa B-dependent transcriptional activity. ET-1 elevated voltage-dependent Ca2+ (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 IP3R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF-kappa B subunit knockdown, leading to vasodilation.
Conclusions: IP3R-mediated SR Ca2+ release elevates [Ca2+](mito), which induces mitoROS generation. MitoROS activate NF-kappa B, which stimulates Ca(V)1.2 channel transcription. Thus, mitochondria sense IP3R-mediated SR Ca2+ release to control NF-kappa B-dependent Ca(V)1.2 channel expression in arterial myocytes, thereby modulating arterial contractility. (Circ Res. 2010;107:631-641.)

• 出版日期2010-9-3