TY - JOUR
T1 - Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity
AU - Wang, Ru Xing
AU - Chai, Qiang
AU - Lu, Tong
AU - Lee, Hon Chi
N1 - Funding Information:
This work was supported by funding from the National Natural Science Foundation of China (81070157 to R.W.), the Basic Medical Institute, Shandong Academy of Medical Sciences (Q.C.), the American Diabetes Association (ADA-JFA-07-39 to T.L.) and the National Institutes of Health (HL080118 and HL074180 to H.L.).
PY - 2011/5/1
Y1 - 2011/5/1
N2 - Aimsn-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochrome P450 (CYP) metabolites of n-3 PUFAs remain virtually unexplored. In this study, we examined the effects of docosahexaenoic acid (DHA) on the regulation of large-conductance calcium-activated potassium (BK) channel activities in coronary arterial smooth muscle cells.Methods and resultsUsing whole-cell patch-clamp techniques, we found that DHA is a potent activator of BK currents in rat coronary arterial smooth muscle cells with an EC50 of 0.23 ± 0.03 M. This effect was abolished by pre-incubation with the CYP epoxygenase inhibitor, SKF525A (10 M). The effects of DHA on the BK channels were reproduced by 16,17-epoxydocosapentaenoic acid (16,17-EpDPE) with an EC50 of 19.7 ± 2.8 nM. The physiological role of the CYP metabolites of DHA was confirmed by measuring DHA-mediated vasodilatation in isolated rat coronary arteries. DHA dilated pressurized isolated coronary arteries in a dose-dependent manner, and the DHA effects were abolished after pre-treatment with SKF525A (10 M) or with iberiotoxin (100 nM). In addition, 16,17-EpDPE directly produced coronary vasodilatation that was iberiotoxin sensitive.ConclusionThese results suggest that DHA-mediated vasodilatation is mediated through CYP epoxygenase metabolites by activation of vascular BK channels.
AB - Aimsn-3 Polyunsaturated fatty acids (PUFAs) are known to protect the cardiovascular system and improve blood pressure control. These important dietary constituents are converted into bioactive metabolites, but their role in regulation of the cardiovascular system is unclear. In particular, the functions of the cytochrome P450 (CYP) metabolites of n-3 PUFAs remain virtually unexplored. In this study, we examined the effects of docosahexaenoic acid (DHA) on the regulation of large-conductance calcium-activated potassium (BK) channel activities in coronary arterial smooth muscle cells.Methods and resultsUsing whole-cell patch-clamp techniques, we found that DHA is a potent activator of BK currents in rat coronary arterial smooth muscle cells with an EC50 of 0.23 ± 0.03 M. This effect was abolished by pre-incubation with the CYP epoxygenase inhibitor, SKF525A (10 M). The effects of DHA on the BK channels were reproduced by 16,17-epoxydocosapentaenoic acid (16,17-EpDPE) with an EC50 of 19.7 ± 2.8 nM. The physiological role of the CYP metabolites of DHA was confirmed by measuring DHA-mediated vasodilatation in isolated rat coronary arteries. DHA dilated pressurized isolated coronary arteries in a dose-dependent manner, and the DHA effects were abolished after pre-treatment with SKF525A (10 M) or with iberiotoxin (100 nM). In addition, 16,17-EpDPE directly produced coronary vasodilatation that was iberiotoxin sensitive.ConclusionThese results suggest that DHA-mediated vasodilatation is mediated through CYP epoxygenase metabolites by activation of vascular BK channels.
KW - 16,17-Epoxydocosapentaenoic acid
KW - BK channel
KW - Coronary arterial smooth muscle cell
KW - Cytochrome P450 epoxygenase
KW - Docosahexaenoic acid
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U2 - 10.1093/cvr/cvq411
DO - 10.1093/cvr/cvq411
M3 - Article
C2 - 21187320
AN - SCOPUS:79955364412
SN - 0008-6363
VL - 90
SP - 344
EP - 352
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -