6-Formylindolo[3,2-b]carbazole (FICZ) protects against angiotensin II-induced cellular hypertrophy through the induction of CYP1A1 and its associated 19(S)-HETE metabolite in vitro .

Aryl hydrocarbon receptor (AhR) is a multifunctional receptor that regulate 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 CYP1A1 mediated AA metabolism and whether it attenuate angiotensin (Ang) II-induced cardiac hypertrophy. Adult human ventricular cardiomyocytes cell line (AC16) treated with FICZ in the presence and absence of Ang II 10 μM. 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-PCR. CYP1A1 enzyme activity and proteasomal degradation were determined by 7-ethoxyresorufin O-deethylase (EROD) and proteasome 20S activity assays, respectively. LC-MS/MS 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 attenuate Ang II-induced cardiac hypertrophy by inhibiting the hypertrophic markers and decreasing cell surface area through midchain-HETEs dependent mechanism. In conclusion, the results demonstrate the ability of FICZ to protects 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 FICZ attenuate Ang II-induced cellular hypertrophy. The novel findings of our investigation are in characterizing the AhR involvement and the enantioselective differences in AA metabolism in cardiac hypertrophy, which opens a new pathway to tackle and eventually treat heart failure.