6-Formylindolo[3,2-b]carbazole Protects Against Angiotensin II-Induced Cellular Hypertrophy through the Induction of Cytochrome P450 1A1 and Its Associated 19(S)-HETE Metabolite In Vitro.

Aryl hydrocarbon receptor (AhR) is a multifunctional receptor that regulates cytochrome P450 1A1 (CYP1A1), an arachidonic acid (AA) metabolizing enzyme producing 19-hydroxyeicosatetraenoic acid (HETE). 6-formylindolo[3,2-b]carbazole (FICZ) demonstrates great affinity toward the AhR. Recently, we have shown that 19(S)-HETE is preferentially cardioprotective. This study investigates the role of FICZ on AhR and cytochrome P450 (CYP) 1A1-mediated AA metabolism and whether it attenuates angiotensin (Ang) II-induced cardiac hypertrophy. Adult human ventricular cardiomyocytes cell line treated with FICZ in the presence and absence of Ang II 10 μ M. Protein levels of AhR and CYPs were determined by Western blot analysis and the mRNA expression of cardiac hypertrophic markers and CYPs were determined by real-time polymerase chain reaction. CYP1A1 enzyme activity and proteasomal degradation were determined by 7-ethoxyresorufin O-deethylase and proteasome 20S activity assays, respectively. Liquid chromatography tandem mass spectrometry was used to measure AA metabolites. Our results show that Ang II-induced cardiac hypertrophy modulates AA metabolites in an enantioselective manner, and that FICZ activates AhR in a time-dependent manner, inhibits AhR proteasomal degradation, induces CYP1A1, increases the concentration of 19(S)-HETE, and attenuates Ang II-induced cardiac hypertrophy by inhibiting the hypertrophic markers and decreasing cell surface area through midchain-HETE-dependent mechanism. In conclusion, the results demonstrate the ability of FICZ to protect against Ang II-induced cardiac hypertrophy by increasing the concentration of 19(S)-HETE through AhR regulated enzyme induction and inhibition of midchain-HETEs metabolites. SIGNIFICANCE STATEMENT: This study shows that 6-formylindolo[3,2-b]carbazole attenuate angiotensin II-induced cellular hypertrophy. The novel findings of our investigation are in characterizing the aryl hydrocarbon receptor involvement and the enantioselective differences in arachidonic acid metabolism in cardiac hypertrophy, which opens a new pathway to tackle and eventually treat heart failure.
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