Resveratrol attenuates angiotensin II-induced cellular hypertrophy through the inhibition of CYP1B1 and the cardiotoxic mid-chain HETE metabolites

Abstract

Several reports demonstrated the direct contribution of cytochrome P450 1B1 (CYP1B1) enzyme and its associated cardiotoxic mid-chain, hydroxyeicosatetraenoic acid (HETEs) metabolites in the development of cardiac hypertrophy. Resveratrol is commercially available polyphenol that exerts beneficial effects in wide array of cardiovascular diseases including cardiac hypertrophy, myocardial infarction and heart failure. Nevertheless, the underlying mechanisms responsible for these effects are not fully elucidated. Since resveratrol is a well-known CYP1B1 inhibitor, the purpose of this study is to test whether resveratrol attenuates angiotensin II (Ang II)-induced cellular hypertrophy through inhibition of CYP1B1/mid-chain HETEs mechanism. RL-14 and H9c2 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 2, 10 or 50 μM resveratrol for 24 h. Thereafter, the level of mid-chain HETEs was determined using liquid chromatography-mass spectrometry (LC/MS). Hypertrophic markers and CYP1B1 gene expression and protein levels were measured using real-time PCR and Western blot analysis, respectively. Our results demonstrated that resveratrol, at concentrations of 10 and 50 μM, was able to attenuate Ang-II-induced cellular hypertrophy as evidenced by substantial inhibition of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide. Ang II significantly induced the protein expression of CYP1B1 and increased the metabolite formation rate of its associated mid-chain HETEs. Interestingly, the protective effect of resveratrol was associated with a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Our results provided the first evidence that resveratrol protects against Ang II-induced cellular hypertrophy, at least in part, through CYP1B1/mid-chain HETEs-dependent mechanism.

Adipokines, Myokines, and Cardiokines: The Role of Nutritional Interventions

“…As reported for adipokines and myokines, different polyphenolic derivatives regulate natriuretic peptides expression. In in vitro and animal studies, resveratrol mitigates cardiac fibrosis improving anti-inflammatory mechanics and downregulating ANP and BNP gene expression [179]. In the same manner, another antioxidative nutraceutical compound, curcumin alleviates cardiac hypertrophy and decreases ANP and BNP gene expression [180].…”

Targeting arachidonic acid–related metabolites in COVID-19 patients: potential use of drug-loaded nanoparticles

“… [ 87 , 106 ] 2-methoxyestradiol A biologically active metabolite of estradiol that has been reported to act as a selective CYP1B1 inhibitor and as a strong anti-inflammatory agent. [ 107 , 108 ] …”

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

“…Ang II model is a well-established approach to study the AA-mediated alterations in cardiac hypertrophy (Alammari et al, 2020;Shoieb and El-Kadi, 2020;Du et al, 2021;Zhao et al, 2022). The concentration of Ang II used in this study is to mimic the cellular hypertrophic model as previously reported (Shoieb and El-Kadi, 2018;Alammari et al, 2020;Gu et al, 2022).…”

“…Of interest, CYP1As, CYP4As and CYP4Fs are linked to the formation of terminal/subterminal-HETE with CYP1A1 being preferentially oxidizing AA to form 19-HETE and one of the CYPs highest activity (El-Sherbeni and El-Kadi, 2014b). The formation of midchain-HETE is reported to be linked to AA metabolism by CYP1B1 (Shoieb and El-Kadi, 2020;Shoieb et al, 2022). It is worth mentioning that there are differences between CYP1A1 and CYP1B1 enzymes towards metabolizing AA to midchain-HETEs.…”

“…To determine the effect of FICZ in cellular cardiac hypertrophy, the hypertrophic markers; β/α MHC, ANP and BNP, as well as cell surface area were investigated in an Ang II model (Alammari et al, 2020;Shoieb and El-Kadi, 2020). They are considered a predictor of ventricular dysfunction and have been reported to be induced in cardiac hypertrophy (Barry et al, 2008).…”