Carfilzomib reverses pulmonary arterial hypertension

Wang, Xinhong; Ibrahim, Yasmine; Das, Dividutta; Zungu-Edmondson, Makhosazane; Shults, Nataliia V.; Suzuki, Yuichiro

doi:10.1093/cvr/cvw047

Cited by 49 publications

(80 citation statements)

References 38 publications

(38 reference statements)

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“…We further found that ubiquitin is essential for carfilzomib-induced cell death and some proteins are ubiquitinated in response to carfilzomib treatment. Mass spectrometry identified that one of the proteins ubiquitinated by carfilzomib is MVP, and this was confirmed by immunopecipitation and immunoblotting [17] . The ubiquitination of MVP is promoted in PAs in response to treating rats with PAH by carfilzomib, but not in healthy control rats [17] .…”

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 74%

“…Mass spectrometry identified that one of the proteins ubiquitinated by carfilzomib is MVP, and this was confirmed by immunopecipitation and immunoblotting [17] . The ubiquitination of MVP is promoted in PAs in response to treating rats with PAH by carfilzomib, but not in healthy control rats [17] . This ubiquitination of MVP in the remodeled pulmonary vasculature with thickened PA smooth muscle was observed in two different rat models of PAH, namely SU5416 injection plus hypoxia and SU5416 injection plus ovalbumin immunization without changing the expression levels of MVP [17] .…”

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 74%

“…We found that carfilzomib effectively killed human PA smooth muscle cells and reversed pulmonary vascular remodeling in intact rats [17] . We further found that ubiquitin is essential for carfilzomib-induced cell death and some proteins are ubiquitinated in response to carfilzomib treatment.…”

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 79%

“…The ubiquitination of MVP is promoted in PAs in response to treating rats with PAH by carfilzomib, but not in healthy control rats [17] . This ubiquitination of MVP in the remodeled pulmonary vasculature with thickened PA smooth muscle was observed in two different rat models of PAH, namely SU5416 injection plus hypoxia and SU5416 injection plus ovalbumin immunization without changing the expression levels of MVP [17] . Summary MVP, the major constituent of vault particles is expressed in cardiac and smooth muscle and may play important roles in cardiovascular pathophysiology.…”

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 88%

“…To our knowledge, studies of MVP in smooth muscle cells (SMCs) had never been conducted until our publications, which show that human airway SMCs [2] and lung vascular SMCs [17] express MVP. Fig.…”

Section: Mvp Is Expressed In Smooth Muscle and Cardiac Musclementioning

confidence: 99%

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Major vault protein in cardiac and smooth muscle

Shults

Das

Suzuki

2016

Receptors Clin Investig

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Major vault protein (MVP) is the major component of the vault particle whose functions are not well understood. One proposed function of the vault is to serve as a mechanism of drug transport, which confers drug resistance in cancer cells. We show that MVP can be found in cardiac and smooth muscle. In human airway smooth muscle cells, knocking down MVP was found to cause cell death, suggesting that MVP serves as a cell survival factor. Further, our laboratory found that MVP is S-glutathionylated in response to ligand/receptor-mediated cell signaling. The S-glutathionylation of MVP appears to regulate protein-protein interactions between MVP and a protein called myosin heavy chain 9 (MYH9). Through MYH9 and Vsp34, MVP may form a complex with Beclin-1 that regulates autophagic cell death. In pulmonary vascular smooth muscle, proteasome inhibition promotes the ubiquitination of MVP, which may function as a mechanism of proteasome inhibition-mediated cell death. Investigating the functions and the regulatory mechanisms of MVP and vault particles is an exciting new area of research in cardiovascular/pulmonary pathophysiology.

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Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 74%

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 74%

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 79%

Section: Post-translational Modifications Of Mvp (Ubiquitination)mentioning

confidence: 88%

Section: Mvp Is Expressed In Smooth Muscle and Cardiac Musclementioning

confidence: 99%

See 3 more Smart Citations

Major vault protein in cardiac and smooth muscle

Shults

Das

Suzuki

2016

Receptors Clin Investig

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Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells

Liu,

Tseng,

Kuan

et al. 2024

The Kaohsiung J of Med Scie

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Pulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)‐approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti‐proliferative and anti‐migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet‐derived growth factor (PDGF)‐BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS‐, Ang II‐ and PDGF‐BB‐induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF‐BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down‐regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH.

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The role of autophagy in pulmonary hypertension: a double-edge sword

Chen

Jiang

et al. 2018

Apoptosis

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Autophagy is a recycling process that degrades damaged or unneeded cellular components for renewal. Accumulating evidence suggests that dysregulation of autophagy is involved in pulmonary hypertension (PH). PH is a progressive disease characterized by persistent proliferation of apoptosis-resistant pulmonary vascular cells. However, reports on the role of autophagy in the development of PH are often conflicting. In this review, we discuss recent development in the field with emphasis on pulmonary arterial endothelial cells, pulmonary smooth muscle cells, right ventricular myocyte, as well as pharmacological strategies targeting the autophagic signaling pathway.

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Carfilzomib reverses pulmonary arterial hypertension

Abstract: The addition of anti-tumour agents such as CFZ along with cardioprotectants to currently available vasodilators may be a promising way to improve PAH therapy.

Cited by 49 publications

References 38 publications

Major vault protein in cardiac and smooth muscle

Major vault protein in cardiac and smooth muscle

Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells

The role of autophagy in pulmonary hypertension: a double-edge sword

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