*3.2. Vascular Endothelial Cells*

With respect to the mechanisms of carfilzomib-associated hypertension, vascular endothelial dysfunction may play a vital role [71–73]. It is known that carfilzomib elicits renal toxic e ffects as well as microangiopathy, which is believed to be mediated by endothelial dysfunction [74–76]. The key feature of vascular endothelial dysfunction is the decreased NO bioavailability, which is caused due to low NO production and/or increased consumption. Provided that endothelial eNOS is responsible for most of the vascular NO produced [77], its dysfunction results in the impairment of endothelium-dependent vasodilatation [78]. Tetrahydrobiopterin (BH4) is known as an essential cofactor for eNOS-mediated NO synthesis [79]. GTP cyclohydrolase (GTPCH), the rate-limiting enzyme involved in BH4 synthesis, has been reported to be regulated by UPS, and that cigarette smoke extract diminished GTPCH abundance that was inhibited by the proteasomal inhibitor MG132 [80]. This BH4 depletion in turn induced eNOS uncoupling with the loss of NO generation and increased superoxide production, resulting in VEC dysfunction [80]. There are also data indicating that UPS-mediated degradation of GTPCH is associated with oxidative stress in angiotensin II-induced hypertension [81] and diabetes mellitus [82]. It was observed that angiotensin II induced the proteasomal degradation of GTPCH via tyrosine nitration of an important regulatory subunit of 26S proteasome, which was triggered by NADPH oxidase activation and generation of free radicals [81]. In another study, streptozotocin-induced diabetic mice displayed reduced eNOS activity, which was restored by the administration of a proteasome inhibitor through the inhibition of the proteasome-dependent GTPCH reduction [82]. These results imply that the UPS-mediated degradation of GTPCH underlies VCE

dysfunction through eNOS regulation. In fact, there have been several reports demonstrating that proteasome inhibitors can improve the function of VECs [83–85]. The role of UPS in endothelial function may vary depending on the disease state and stage, and further studies are required to investigate the role of UPS in VECs.
