PT  - JOURNAL ARTICLE
AU  - Sherif M. Shoieb
AU  - Ayman O. S. El-Kadi
TI  - <em>S-</em>Enantiomer of 19-Hydroxyeicosatetraenoic Acid Preferentially Protects Against Angiotensin II-Induced Cardiac Hypertrophy
AID  - 10.1124/dmd.118.082073
DP  - 2018 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 1157--1168
VI  - 46
IP  - 8
4099  - http://dmd.aspetjournals.org/content/46/8/1157.short
4100  - http://dmd.aspetjournals.org/content/46/8/1157.full
SO  - Drug Metab Dispos2018 Aug 01; 46
AB  - We had recently demonstrated that the racemic mixture of 19-hydroxyeicosatetraenoic acid (19-HETE) protects against angiotensin II (Ang II)-induced cardiac hypertrophy. Therefore, the purpose of this study was to investigate whether the R- or S-enantiomer of 19-HETE confers cardioprotection against Ang II-induced cellular hypertrophy in RL-14 and H9c2 cells. Both cell lines were treated with vehicle or 10 μM Ang II in the absence and presence of 20 μM 19(R)-HETE or 19(S)-HETE for 24 hours. Thereafter, the level of midchain HETEs was determined using liquid chromatography–mass spectrometry. Gene- and protein-expression levels were measured using real-time polymerase chain reaction and Western blot analysis, respectively. The results showed that both 19(R)-HETE and 19(S)-HETE significantly decreased the metabolite formation rate of midchain HETEs, namely 8-, 9-, 12-, and 15-HETE, compared with control group, whereas the level of 5-HETE was selectively decreased by S-enantiomer. Moreover, both 19(R)-HETE and 19(S)-HETE significantly inhibited the catalytic activity of CYP1B1 and decreased the protein expression of 5- and 12-lipoxygenase (LOX) as well as cyclo-oxygenase-2 (COX-2). Notably, the decrease in 15-LOX protein expression was only mediated by 19(S)-HETE. Interestingly, both enantiomers protected against Ang II-induced cellular hypertrophy, as evidenced by a significant decrease in mRNA expression of β/α-myosin heavy chain ratio, atrial natriuretic peptide, and interleukins 6 and 8. Our data demonstrated that S-enantiomer of 19-HETE preferentially protected against Ang II-induced cellular hypertrophy by decreasing the level of midchain HETEs, inhibiting catalytic activity of CYP1B1, decreasing protein expression of LOX and COX-2 enzymes, and decreasing mRNA expression of IL-6 and IL-8.