Cell migration, protection of endothelial cells against hypoxia-reoxygenation injury, upregulation of
Cell migration, protection of endothelial cells against hypoxia-reoxygenation injury, upregulation of endothelial nitric oxide biosynthesis, and protection of doxorubicin-induced cardiotoxicity (Larsen et al., 2007; Spector and Norris, 2007; Yang et al., 2009; Zhang et al., 2009; Campbell and αLβ2 Compound Fleming, 2010; Pfister et al., 2010). All these events are involved in cardiac electrophysiology and protect the heart from ischemic-reperfusion injury (Spiecker and Liao, 2006). Additional especially, the regioisomer 11,12-EET has been shown to be a potent activator with the ion channels sensitive to ATP, to straight decrease the membrane action potential in rat myocytes (Lu et al., 2001), and to boost recovery of ventricular repolarization following ischemia reperfusion injury (Batchu et al., 2009). These investigations considerably improved interest in CYP2J2 with regard to its enzymology, localized expression, as well as the need for an in vitro model method suitable for studying the enzyme’s value in preserving cardiomyocyte homeostasis.This operate was supported by the National Institutes of Wellness National Heart, Lung and Blood Institute [R01HL096706]. dx.doi.org/10.1124/dmd.113.053389. s This short article has supplemental material accessible at dmd.aspetjournals.org.CYP2J2 is predominantly expressed in extrahepatic tissues, specifically inside the heart, but in addition in skeletal muscle, placenta, little intestine, kidney, lung, pancreas, bladder, and brain (Wu et al., 1997; Zeldin et al., 1997; Bieche et al., 2007). While a crystal structure has however to become elucidated, molecular models suggest structural similarity in between CYP2J2 and CYP3A4, explaining why the two enzymes share numerous substrates of diverse therapeutic locations, for instance the antihistamine drugs terfenadine, astemizole, and ebastine (Matsumoto and Yamazoe, 2001; Hashizume et al., 2002; Matsumoto et al., 2002; Liu et al., 2006; Lafite et al., 2007), anticancer drug tamoxifen, and drugs such as thioridazine or cyclosporine (Lee et al., 2012). The combination of cardiac localization and involvement in the arachidonic acid metabolism makes CYP2J2 a specifically exciting target to mechanistically investigate drug-induced cardiotoxicity. So far, no studies have demonstrated drug metabolism within the heart tissue. The inhibitory or inductive effect by such drugs on arachidonic acid metabolism could have profound downstream consequences by decreasing EETs and their protective properties. Even so, a human heart model remains elusive and testing relies on animal-model, specially dog, cell systems or PLK3 Formulation recombinant enzymes. Significantly of CYP2J2’s activity has been assessed in such models as Escherichia coli-expressed or Baculovirus-infected insect cell xpressed enzyme (Supersomes) (Lafite et al., 2007), human liver microsomes (Lee et al., 2012), or in humanized animal models that overexpress the enzyme in cardiac tissue (Seubert et al., 2004; Deng et al., 2011). In this study, we evaluate commercially accessible main human cardiomyocytes for expression and activity of CYP2J2. We initial clonedABBREVIATIONS: BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; CE, collision energy; CPR, cytochrome P450 reductase; DMSO, dimethylsulfoxide; DP, declustering prospective; EET, epoxyeicosatrienoic acid; hPSC, human pluripotent stem cells; hPSC-CMs, hPSCderived cardiomyocytes; LC, liquid chromatography; MS/MS, tandem mass spectrometry; P450, cytochrome P450; PBS, phosphate-buffered saline; PXR, pregnane X receptor.Evangelist.