Aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole attenuates pressure overload cardiac hypertrophy by activating the CYP1A1/19(S)-hydroxyeicosatetraenoic acid (HETE) and suppressing midchain-HETEs/G protein coupled receptor 31 pathways.

Pressure overload induced cardiac hypertrophy is a major contributor to heart failure, and the arachidonic acid (AA) metabolism through cytochrome P450 enzymes is one of the metabolic pathways implicated in the hypertrophic response. The aryl hydrocarbon receptor (AhR) regulates CYP1A1 and CYP1B1 that generate protective 19-hydroxyeicosatetraenoic (HETE) and hypertrophic midchain-HETEs eicosanoids, respectively. The endogenous AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ) is a potent and selective inducer of CYP1A1, but its role in pressure overload induced cardiac hypertrophy has not been examined. This study investigated whether daily AhR activation by FICZ alters AA metabolites and attenuates cardiac hypertrophy in the abdominal aortic constriction (AAC) model. Male Sprague-Dawley rats underwent AAC or sham surgery and received FICZ (0.2 mg/kg per day) for 5 weeks. Echocardiography was performed at baseline and 5 weeks post-AAC, and gene, protein, and midchain-HETEs levels were assessed by real-time polymerase chain reaction, western blot, and liquid chromatography-tandem mass spectrometry, respectively. FICZ significantly reduced AAC-induced increases in left ventricular mass, ventricular wall thickness, heart weight-to-tibial length ratio, and hypertrophic gene expression. FICZ produced selective induction of CYP1A1 and significant rise in cardiac 19(S)-HETE. AAC significantly increased CYP1B1 and 12-LOX protein expressions and midchain-HETEs, whereas FICZ significantly attenuated 12-LOX and midchain-HETE. AAC also upregulated G protein coupled receptor 31, and FICZ reduced this increase at both mRNA and protein levels. This study provides the first evidence that endogenously generated 19(S)-HETE is cardioprotective in a pressure overload model and identifies FICZ as a modulator of the CYP1A1/19(S)-HETE that suppresses midchain-HETEs/G protein coupled receptor 31 pathways. SIGNIFICANT STATEMENT: This study demonstrates that 6-formylindolo[3,2-b]carbazole protect against cardiac hypertrophy induced by abdominal aortic constriction in rats. The significance of this research lies in its novel discovery, which elucidates for the first time the involvement of G protein coupled receptor 31 and the induction of CYP1A1 and 19-hydroxyeicosatetraenoic acid and suppressing midchain-hydroxyeicosatetraenoic acid/G protein coupled receptor 31 pathways by 6-formylindolo[3,2-b]carbazole in the protection against pressure overload cardiac hypertrophy in rats.