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Vascular mitochondrial dysfunction associated with insulin resistance impairs activation of Ca 2+ ‐sparks and mitochondrial Ca 2+ uptake
Author(s) -
Katakam Prasad V.G,
Snipes James A,
Busija David W
Publication year - 2011
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.25.1_supplement.1095.16
Subject(s) - protonophore , reactive oxygen species , mitochondrion , vasodilation , diazoxide , chemistry , medicine , endocrinology , insulin resistance , depolarization , biology , insulin , biochemistry
Mitochondrial depolarization (MD) and subsequent generation of reactive oxygen species (ROS) have been shown to trigger vasodilation via activation of ‘Ca 2+ sparks' (CS) and Ca 2+ ‐activated K + channels. Previously, we reported reduced MD and ROS generation and mitochondria mediated vasodilation in insulin resistant (IR) Zucker obese (ZO) compared to lean (ZL) rats. Therefore, we evaluated the impact of mitochondrial dysfunction on CS activation and mitochondrial Ca 2+ (mitoCa 2+ ) in cerebral artery smooth muscle cells (SMC) utilizing fluoroprobes Fluo‐4 AM and Rhod‐2AM, respectively. MD with or without accompanying ROS generation was achieved by putative mitochondrial K ATP channel activators 100 μM diazoxide (DZ) or 50 μM BMS‐191095 (BMS), respectively. Baseline CS activity (sparks/min) was reduced in ZO compared to ZL (156±21 versus 231±26, p<0.05). BMS and DZ responses were diminished in ZO (207±48 and 257±32, p=NS) versus ZL (318±54 and 366±63). BMS and DZ promoted greater increase in mitoCa 2+ in SMCs of ZL compared to ZO. The protonophore carbonyl cyanide m‐chlorophenylhydrazone (10 μM) abolished CS and diminished mitoCa 2+ in all arteries. Thus, mitochondrial dysfunction associated with IR impaired CS activity and mitoCa 2+ uptake leading to reduced mitochondria mediated vasodilation. Supported by NIH (HL‐093554, HL‐030260, HL‐065380).