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The role of cytochrome P450 1B1 and its associated mid‐chain hydroxyeicosatetraenoic acids metabolites in the development of cellular hypertrophy induced by isoproterenol
Author(s) -
ElKadi Ayman O.S.,
Maayah Zaid H.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1198.5
Subject(s) - hydroxyeicosatetraenoic acid , muscle hypertrophy , cyp1b1 , endocrinology , chemistry , medicine , biology , cytochrome p450 , microbiology and biotechnology , biochemistry , metabolism , enzyme , lipoxygenase
Heart failure is the leading cause of death, with a prevalence of over 23 million worldwide. The lifetime risk of developing heart failure is one in five. Numerous experimental studies have demonstrated the role cytochrome P450 1B1 (CYP1B1) and its associated mid‐chain hydroxyeicosatetraenoic acids (mid‐chain HETEs) metabolites in the pathogenesis of heart failure and cardiac hypertrophy. However, the ability of isoproterenol (ISO) to induce cardiac hypertrophy through mid‐chain HETEs has not been investigated yet. Therefore, we hypothesized that ISO induced cardiac hypertrophy through the induction of CYP1B1 and its associated mid‐chain HETEs metabolites. To test our hypothesis, the human ventricular cardiomyocytes, RL‐14 cells, were treated with ISO in the presence and absence of tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, the cellular hypertrophy markers, cell volume and mid‐chain HETEs metabolites were determined using real‐time polymerase chain reaction, phase contrast imaging and liquid chromatography‐electron spray ionization‐mass spectrometry, respectively. Our results showed that ISO induced cellular hypertrophy in RL‐14 cells as evidenced by the significant induction of β‐myocin heavy chain/α‐myocin heavy chain (β‐MHC/α‐MHC) and cell volume. Interestingly, ISO‐induced cellular hypertrophy was associated with a proportional increase in the protein expression of CYP1B1 and the formation of mid‐chain HETEs metabolites. The direct evidence for the involvement of CYP1B1 in the ISO‐induced cellular hypertrophy was supported by the ability of TMS and CYP1B1 siRNA to significantly inhibit the ISO‐mediated the induction of β‐MHC/α‐MHC and the increase cell volume. Mechanistically, the protective effect of TMS against ISO‐induced cellular hypertrophy was mediated through the inhibition of NF‐κB signaling pathway. In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and hence mid‐chain HETEs attenuate ISO‐induced cellular hypertrophy. Support or Funding Information This work was supported by a grant from the CIHR to A.O.S.E.