期刊
CARDIOVASCULAR RESEARCH
卷 95, 期 2, 页码 183-193出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs128
关键词
Vascular smooth muscle cells; Ubiquitinproteasome system; Proteolysis; Endoplasmic reticulum stress; Redox processes
资金
- Instituto Nacional de Ciencia, Tecnologia e Inovacao de Processos Redox (INCT - Redoxoma)
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
- Conselho Nacional de Pesquisa (CNPq)
Vascular smooth muscle cell (VSMC) plasticity implies a capacity for rapid change and adaptability through processes requiring protein turnover. The ubiquitinproteasome system (UPS) is at the core of protein turnover as the main pathway for the degradation of proteins related to cell-cycle regulation, signalling, apoptosis, and differentiation. This review briefly addresses some structural UPS aspects under the perspective of VSMC (patho)biology. The UPS loss-of-function promotes direct cell effects and many indirect effects related to the adaptation to apoptosis/survival signalling, oxidative stress, and endoplasmic reticulum stress. The UPS regulates redox homeostasis and is redox-regulated. Also, the UPS closely interacts with endoplasmic reticulum (ER) homeostasis as the effector of un/misfolded protein degradation, and ER stress is strongly involved in atherosclerosis. Inhibition of cell cycle-controlling ubiquitin ligases or the proteasome reduces VSMC proliferation and prevents modulation of their synthetic phenotype. Proteasome inhibition also strongly promotes VSMC apoptosis and reduces neointima. In atherosclerosis models, proteasome inhibitors display vasculoprotective effects and reduce inflammation. However, worsening of atherosclerosis or vascular dysfunction has also been reported. Proteasome inhibitors sensitize VSMC to increased ER stress-mediated cell death and suppress unfolded protein response signalling. Taken together, these observations show that the UPS has powerful effects in the control of VSMC phenotype and survival signalling. However, more profound knowledge of mechanisms is needed in order to render the UPS an operational therapeutic target.
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