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Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
Published on: August 2, 2018
Proteasome Inhibitors Decrease the Viability of Pulmonary Arterial Smooth Muscle Cells by Restoring Mitofusin-2
I-Chen Chen1,2,3, Yi-Ching Liu1, Yen-Hsien Wu1
1Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan.
Abstract:
Pulmonary hypertension (PH) is a severe progressive disease, and the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the main causes. Mitofusin-2 (MFN2) profoundly inhibits cell growth and proliferation in a variety of tumor cell lines and rat vascular smooth muscle cells. Down-regulation of MFN2 is known to contribute to PH. Proteasome inhibitors have been shown to inhibit the proliferation of PASMCs; however, there is no study on the regulation of proteasome inhibitors through MFN-2 in the proliferation of PASMCs, a main pathophysiology of PH. In this study, PASMCs were exposed to hypoxic conditions and the expression of MFN2 and cleaved-PARP1 were detected by Western blotting. The effects of hypoxia and proteasome inhibitors on the cell viability of PASMC cells were detected by CCK8 assay. The results indicated that hypoxia increases the viability and reduces the expression of MFN2 in a PASMCs model. MFN2 overexpression inhibits the hypoxia-induced proliferation of PASMCs. In addition, proteasome inhibitors, bortezomib and marizomib, restored the decreased expression of MFN2 under hypoxic conditions, inhibited hypoxia-induced proliferation and induced the expression of cleaved-PARP1. These results suggest that bortezomib and marizomib have the potential to improve the hypoxia-induced proliferation of PASMCs by restoring MFN2 expression.
Insights
Pulmonary hypertension involves uncontrolled pulmonary artery smooth muscle cell (PASMC) proliferation. Mitofusin-2 (MFN2) inhibits this growth, and proteasome inhibitors may restore MFN2 levels to combat PH.
Area of Science:
- Cardiovascular Research
- Cell Biology
- Molecular Medicine
Background:
- Pulmonary hypertension (PH) is a severe disease driven by pulmonary artery smooth muscle cell (PASMC) overgrowth.
- Mitofusin-2 (MFN2) normally inhibits cell proliferation, and its reduced expression is linked to PH.
- The role of MFN2 in regulating PASMC proliferation under hypoxic conditions and the impact of proteasome inhibitors remain unclear.
Purpose of the Study:
- To investigate the role of MFN2 in hypoxia-induced PASMC proliferation.
- To determine if proteasome inhibitors can modulate MFN2 expression and affect PASMC proliferation in a PH model.
Main Methods:
- PASMCs were subjected to hypoxic conditions.
- Western blotting was used to detect MFN2 and cleaved-PARP1 expression.
- CCK8 assay measured cell viability and proliferation.
Main Results:
- Hypoxia increased PASMC viability and decreased MFN2 expression.
- Overexpression of MFN2 inhibited hypoxia-induced PASMC proliferation.
- Proteasome inhibitors (bortezomib, marizomib) restored MFN2 levels, inhibited proliferation, and increased cleaved-PARP1.
Conclusions:
- MFN2 plays a crucial role in inhibiting hypoxia-induced PASMC proliferation.
- Proteasome inhibitors show potential therapeutic value in PH by restoring MFN2 expression and reducing PASMC overgrowth.
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