Arginase Inhibition Mitigates Bortezomib-Exacerbated Cardiotoxicity in Multiple Myeloma

• Published in: Cancers Vol. 15; no. 7; p. 2191
• Main Authors: Paterek, Aleksandra, Oknińska, Marta, Pilch, Zofia, Sosnowska, Anna, Ramji, Kavita, Mackiewicz, Urszula, Golab, Jakub, Nowis, Dominika, Mączewski, Michał
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06-04-2023; MDPI
• Subjects: Amino acids; Arginase; Bone marrow; Bortezomib; Cardiotoxicity; Cardiovascular diseases; Complications and side effects; Coronary artery disease; Dosage and administration; Drug therapy; Echocardiography; Ejection fraction; Endothelium; Health aspects; Heart diseases; Heart failure; Hypertension; Hypotheses; Malignancy; Medical prognosis; Medical research; Morbidity; Mortality; Multiple myeloma; Nitric oxide; Plasma; Proteasome inhibitors; Proteasomes; Proteins; Statistical analysis; Variance analysis; Ventricle; Poland; United States > US; endothelial function; arginase inhibitor; cardiotoxicity; multiple myeloma; nitric oxide; bortezomib
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15072191

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.
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.
We used a mouse Vĸ*MYC model of non-light chain MM. Cardiac function was assessed by echocardiography.
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.
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.