The
extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte
hypertrophy and is cardioprotective, with the three
RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human
heart failure, whether BRAF promotes cardiomyocyte
hypertrophy, and if Type 1 RAF inhibitors developed for
cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with
heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with
tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced
cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant
fibrosis, consistent with compensated
hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or
encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted
hypertrophy, consistent with a 'RAF paradox' effect. Both promoted
cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt
fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce
hypertrophy, and Type 1 RAF inhibitors promote
hypertrophy via the 'RAF paradox'.
Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.