Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma

SIMPLE SUMMARY: Multiple myeloma is a hematological malignancy associated with increased cardiovascular morbidity and mortality. Its therapies also result in adverse cardiac effects. Since multiple myeloma is associated with increased expression of arginase, an enzyme that consumes an amino acid arginine, a precursor for nitric oxide synthesis, our aim was to test if cardiotoxicity mediated by multiple myeloma and one of its most commonly used therapies, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved vascular nitric oxide system. We used a mouse Vĸ*MYC model of multiple myeloma. The disease resulted in progressive cardiac dysfunction, and bortezomib exacerbated this effect. An arginase inhibitor protected the heart against bortezomib- or multiple myeloma-induced toxicity but did not completely prevent the effects of the multiple myeloma+bortezomib combination. Neither multiple myeloma nor bortezomib impaired vascular nitric oxide system. Our study suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the nitric oxide pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in multiple meyloma. ABSTRACT: Background: Multiple myeloma (MM) is associated with increased cardiovascular morbidity and mortality, while MM therapies also result in adverse cardiac effects. Endothelial dysfunction and impaired nitric oxide (NO) pathway is their possible mediator. Objective: Since MM is associated with increased arginase expression, resulting in the consumption of ʟ-arginine, precursor for NO synthesis, our aim was to test if cardiotoxicity mediated by MM and MM therapeutic, bortezomib (a proteasome inhibitor), can be ameliorated by an arginase inhibitor through improved endothelial function. Methods: We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography. Results: MM resulted in progressive left ventricular (LV) systolic dysfunction, and bortezomib exacerbated this effect, leading to significant impairment of LV performance. An arginase inhibitor, OAT-1746, protected the heart against bortezomib- or MM-induced toxicity but did not completely prevent the effects of the MM+bortezomib combination. MM was associated with improved endothelial function (assessed as NO production) vs. healthy controls, while bortezomib did not affect it. OAT-1746 improved endothelial function only in healthy mice. NO plasma concentration was increased by OAT-1746 but was not affected by MM or bortezomib. Conclusions: Bortezomib exacerbates MM-mediated LV systolic dysfunction in a mouse model of MM, while an arginase inhibitor partially prevents it. Endothelium does not mediate either these adverse or beneficial effects. This suggests that proteasome inhibitors should be used with caution in patients with advanced myeloma, where the summation of cardiotoxicity could be expected. Therapies aimed at the NO pathway, in particular arginase inhibitors, could offer promise in the prevention/treatment of cardiotoxicity in MM.