Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 299, Issue 4, Pages H1109-H1117Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00067.2010
Keywords
20-hydroxyeicosatetraenoic acid; L-type calcium channel; protein kinase C; cardiac myocytes; reactive oxygen species
Funding
- American Heart Association [0635050N]
- National Natural Science Foundation of China [30870910]
- National Center for Research Resources [2P20-RR-015566]
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Zeng Q, Han Y, Bao Y, Li W, Li X, Shen X, Wang X, Yao F, O'Rourke ST, Sun C. 20-HETE increases NADPH oxidase-derived ROS production and stimulates the L-type Ca2+ channel via a PKC-dependent mechanism in cardiomyocytes. Am J Physiol Heart Circ Physiol 299: H1109-H1117, 2010. First published July 30, 2010; doi:10.1152/ajpheart.00067.2010.-The production of 20-hydroxyeicosatetraenoic acid (20-HETE) is increased during ischemia-reperfusion, and inhibition of 20-HETE production has been shown to reduce infarct size caused by ischemia. This study was aimed to discover the molecular mechanism underlying the action of 20-HETE in cardiac myocytes. The effect of 20-HETE on L-type Ca2+ currents (I-Ca,I-L) was examined in rat isolated cardiomyocytes by patch-clamp recording in the whole cell mode. Superfusion of cardiomyocytes with 20-HETE (10-100 nM) resulted in a concentration-dependent increase in I-Ca,I-L, and this action of 20-HETE was attenuated by a specific NADPH oxidase inhibitor, gp91ds-tat (5 mu M), or a superoxide scavenger, polyethylene glycol-superoxide dismutase (25 U/ml), suggesting that NADPH-oxidase-derived superoxide is involved in the stimulatory action of 20-HETE on I-Ca,I-L. Treatment of cardiomyocytes with 20-HETE (100 nM) increased both NADPH oxidase activity and superoxide production by approximately twofold. To study the molecular mechanism mediating the 20-HETE-induced increase in NADPH oxidase activity, PKC activity was measured in cardiomyocytes. Incubation of the cells with 20-HETE (100 nM) significantly increased PKC activity, and pretreatment of cardiomyocytes with a selective PKC inhibitor, GF-109203 (1 mu M), attenuated the 20-HETE-induced increases in I-Ca,I-L and in NADPH oxidase activity. In summary, 20-HETE stimulates NADPH oxidase-derived superoxide production, which activates L-type Ca2+ channels via a PKC-dependent mechanism in cardiomyocytes. 20-HETE and 20-HETE-producing enzymes could be novel targets for the treatment of cardiac ischemic diseases.
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