Doxorubicin-induced vascular toxicity : investigating the underlying mechanisms and its temporal relationship to cardiotoxicity
Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) induces vascular toxicity, represented mainly by arterial stiffness and endothelial dysfunction. Arterial stiffness and endothelial dysfunction are independent predictors of and important contributors to cardiovascular disease in the general population. Here, using a DOX-treated murine model, we investigated the mechanisms underlying DOX-induced arterial stiffness and endothelial dysfunction and their contribution to cardiovascular disease, and evaluated whether these parameters could serve as early markers of cardiotoxicity. To this end, in vivo cardiovascular function and ex vivo arterial stiffness and vascular reactivity were evaluated during and after DOX therapy (4 mg/kg/week for six weeks). DOX decreased left ventricular systolic function by 10%, defined as moderate cardiotoxicity, which persisted during follow-up. Blood pressure did not change. DOX induced arterial stiffness and endothelial dysfunction, which recovered during treatment and follow-up, respectively. Importantly, both DOX-induced arterial stiffness and endothelial dysfunction preceded cardiotoxicity. Mechanistically, DOX provokes vascular toxicity through a complex, successive alteration of both active and passive components that collectively modulate arterial stiffness over time. First, DOX impairs endothelial function by decreasing expression of endothelial nitric oxide synthase, a key enzyme for production of the vasodilator nitric oxide. This, in turn, enhances vascular tone, thereby augmenting arterial stiffness. Soon thereafter, extracellular matrix remodeling occurs due to differential expression of several extracellular glycoproteins, particularly SERPINA3 and THBS1, which may mediate DOX-induced arterial stiffness recovery. SERPINA3 and THBS1 levels remained higher after therapy cessation. When quantified in plasma, SERPINA3 and THBS1 levels were elevated in cancer survivors with anthracycline-induced cardiotoxicity as well, and showed an inverse correlation with systolic function. Finally, we investigated whether DOX-induced vascular toxicity directly exacerbates atherosclerotic plaque formation. Plaque amount and content were determined in male and female apolipoprotein-E-deficient mice on a high-fat diet where DOX (4 mg/kg) or vehicle (saline) was intraperitoneally administered weekly for three weeks during the diet. Overall, plaque amount/content did not differ along the arterial tree among treatment groups. In conclusion, DOX transiently induced arterial stiffness and endothelial dysfunction, which both preceded persistently impaired cardiac function, placing these parameters as potential early, but time-sensitive, functional markers of future cardiotoxicity in patients receiving DOX. Additionally, our data indicate a possible role for SERPINA3 and THBS1 in DOX-induced cardiovascular toxicity with promising diagnostic value for DOX-treated patients. Finally, our data suggest that, at least in the acute and short-term follow-up phases, DOX-induced vascular toxicity does not potentiate cardiotoxicity, hypertension and atherosclerosis.
Antwerpen : Universiteit Antwerpen, Faculteit Geneeskunde en Gezondheidswetenschappen , 2023
245 p.
Supervisor: Guns, Pieter-Jan D.F. [Supervisor]
Supervisor: van Craenenbroeck, Emeline M. [Supervisor]
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Project info
Discovering the role of titin (TTN) in anthracycline-induced cardiac dysfunction in breast cancer.
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Publications with a UAntwerp address
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Creation 19.09.2023
Last edited 11.10.2023
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