Affiliation:
1. From the Departments of Physiology (D.N., Q.X., J.H.J.) and Pathology and Laboratory Medicine (L.M.P.), University of Tennessee Health Science Center, Memphis.
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)-κB p50 subunit and ET-1–induced IP
3
R-mediated mitoROS elevated NF-κB–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-κB 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-κB, which stimulates Ca
V
1.2 channel transcription. Thus, mitochondria sense IP
3
R-mediated SR Ca
2+
release to control NF-κB–dependent Ca
V
1.2 channel expression in arterial myocytes, thereby modulating arterial contractility.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
61 articles.
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