Fluconazole Protects against Abdominal Aortic Constriction‐Induced Cardiac Hypertrophy

Abstract

Purpose: Cytochrome P450 1B1 (CYP1B1) is known to be involved in the pathogenesis of several cardiovascular diseases such as cardiac hypertrophy and heart failure, through the formation of cardiotoxic metabolites named as midchain hydroxyeicosatetraenoic acids (HETEs). Recently, we have demonstrated that fluconazole, an antifungal agent, decreases the level of mid-chain HETEs in human liver microsomes, inhibits human recombinant CYP1B1 activity and protects against angiotensin II-induced cellular hypertrophy in H9c2 cells. Therefore, the overall objectives of the present study were to elucidate the potential cardioprotective effect of fluconazole against cardiac hypertrophy induced by abdominal aortic constriction (AAC) and unravel the mechanism(s) involved. Methods: Male Sprague-Dawley rats were randomly assigned into four groups; sham control rats, fluconazole-treated (20 mg/kg daily for 4 weeks, intraperitoneal) sham rats, AAC rats and fluconazole-treated (20 mg/kg) AAC rats. Baseline and 5 weeks post-AAC echocardiography were performed. Gene and protein expression were measured using real-time PCR and Western blot analysis, respectively. The level of mid-chain HETEs was determined using liquid chromatography–mass spectrometry (LC/MS). Results: Echocardiography results showed that fluconazole significantly reversed the AAC-induced left ventricular hypertrophy, as it was able to ameliorate the AAC-mediated increase in left ventricular mass and several wall measurements. In addition, fluconazole significantly prevented the AAC-mediated increase of hypertrophic markers, β-myosin heavy chain (MHC)/α-MHC and atrial natriuretic peptide (ANP). The antihypertrophic effect of fluconazole was associated with a significant inhibition of CYP1B1 at the gene and protein levels as well as a reduction in the formation rate of midchain HETEs. Conclusion: The current study demonstrates a strong evidence that fluconazole protects against left ventricular hypertrophy. The findings of the present work highlight the potential repurposing of fluconazole as a CYP1B1 inhibitor for the protection against cardiac hypertrophy and a possible treatment for heart failure.