haracterisation of the involvement of angiotensin-signalling pathways in anthracycline-induced cardiotoxicity

Abstract

Delayed cardiotoxicity is a major clinical issue with anthracyclines and cancer treatment, associated with development of life-threatening heart failure. Clinically, drugs interfering with the angiotensin-signalling pathway have shown promise for mitigation of anthracycline induced cardiotoxicity (AIC). However, the mechanistic basis for this response remains unclear. In this study, both angiotensin II stimulation and exposure to sub-therapeutic concentrations of the anthracycline doxorubicin have been shown to induce cellular hypertrophy in human cardiomyocyte cells, an effect associated with a significant upregulation of expression of the angiotensin receptor (AT1R). In contrast, no such morphological changes were observed in primary human cardiac fibroblasts (HCF). Surprisingly, despite no observable structural change being detected in HCF, exposure to doxorubicin did cause an increase in AT1R expression. Such an observation indicating a potential interplay between these two cell types of the myocardium in AIC, involving crosstalk of the angiotensin-signalling pathway. The importance for AT1R in the cardiomyocyte response to doxorubicin was confirmed by knockdown of AT1R using small interfering RNA (siRNA), which mitigated the hypertrophic response. From a therapeutic perspective, the hypertrophic response of cardiomyocytes was mitigated by pre-exposure to the angiotensin receptor blocking drug telmisartan, offering an explanation for the cardioprotective effects of blocking angiotensin-signalling in AIC. Together these findings support an involvement for angiotensin signalling in drug-induced hypertrophy and subsequent cardiotoxicity, with scope for interaction of this pathway for mitigation of chronic cardiotoxicity in the clinic.