The anti-cancer drug trametinib suppresses angiotensin-induced cardiac remodelling in mice but is detrimental to function

Cooper, S. T.; Duvenage, E.; Gattari, D.; Cull, J. J.; Dash, P. R.; Chan, D.; Soria, M. L.; Rossi, M.; Nasuto, S. J.; Holderbaum, W.; Kelion, A.; Sugden, P. H.; Glennon, P. E.; Clerk, A.

doi:10.1101/2025.05.16.654397

bioRxiv · 10.1101/2025.05.16.654397

The anti-cancer drug trametinib suppresses angiotensin-induced cardiac remodelling in mice but is detrimental to function

Cooper, S. T.·Duvenage, E.·Gattari, D.·Cull, J. J.·Dash, P. R.·Chan, D.·Soria, M. L.·Rossi, M.·Nasuto, S. J.·Holderbaum, W.·Kelion, A.·Sugden, P. H.·Glennon, P. E.·Clerk, A.

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Abstract

Aims. Echocardiography is used widely in preclinical mouse studies, but the emphasis remains the histological/pathological/biochemical changes in the myocardium. Analysis/reporting of cardiac function is generally limited, often relying on M-mode assessment of a single plane across the left ventricle. The aim was to determine if global/segmental endocardial speckle-tracking (strain) has greater potential to assess function by distinguishing between mouse lines and identifying regional effects of different drugs. Methods and results. Echocardiograms from male C57Bl/6J (commercially-available) or C57Bl/6(R) (bred in-house) mice treated with vehicle or angiotensin II (AngII; 0.8 mg/kg/d, 7 d) were analysed. Global strain demonstrated different degrees of hypertrophy induced by AngII in the different lines, and variation in function (e.g. stroke volume/cardiac output were reduced in C57Bl/6J mice only, with no effect on global longitudinal strain). For C57Bl/6J mice, segmental strain (radial/longitudinal peak displacement/velocity/strain/strain rate) and frame-to-frame analysis of radial/longitudinal displacement identified more significant effects of AngII in the basal/mid-regions of the left ventricle. Thus, speckle-tracking distinguished between responses in different mouse lines. The methodology was applied to studies of anti-cancer drugs that inhibit extracellular signal-regulated kinase 1/2 signalling. Dabrafenib and/or trametinib inhibited AngII-induced cardiac hypertrophy, but dabrafenib alone caused abnormalities in endocardial movement whilst, for trametinib with AngII, more abnormalities were detected than with AngII alone. For both, the dominant effect was in the basal/mid-regions of the left ventricle. Conclusion. Echocardiography in preclinical studies can be exploited using endocardial segmental strain for greater insight into how drugs affect cardiac function in different regions of the left ventricle.

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Cooper, S. T., Duvenage, E., Gattari, D., Cull, J. J., Dash, P. R., Chan, D., Soria, M. L., Rossi, M., Nasuto, S. J., Holderbaum, W., Kelion, A., Sugden, P. H., Glennon, P. E., Clerk, A.. 2025-05-20. The anti-cancer drug trametinib suppresses angiotensin-induced cardiac remodelling in mice but is detrimental to function. https://doi.org/10.1101/2025.05.16.654397

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