Diminished arachidonate 5-lipoxygenase perturbs phase separation and transcriptional response of Runx2 to reverse pathological ventricular remodeling

Untargeted metabolomics showed that serum 5-HETE (a primary product of Alox5) levels were little changed in patients with cardiac hypertrophy, while Alox5 expression was significantly upregulated in murine hypertensive cardiac samples and human cardiac samples of hypertrophy, which prompted us to test whether high Alox5 levels under hypertensive stimuli were directly associated with pathologic myocardium in an enzymatic activity-independent manner. Herein, we revealed that Alox5 deficiency significantly ameliorated transverse aortic constriction (TAC)-induced hypertrophy. Cardiomyocyte-specific Alox5 depletion attenuated hypertensive ventricular remodeling. Conversely, cardiac-specifical Alox5 overexpression showed a pro-hypertrophic cardiac phenotype. Ablation of Alox5 in bone marrow-derived cells did not affect pathological cardiac remodeling and heart failure. To clarify the specific mechanisms by which Alox5 regulates cardiac hypertrophy, we generated cardiac Alox5 deficient mouse.