Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival
Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of <i>protein disulfide isomerase 4</i> (<i>PDIA-4</i>); however, its role in endothelial cells is not kn...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3913 |
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| author | Shuhan Bu Aman Singh Hien C. Nguyen Bharatsinai Peddi Kriti Bhatt Naresh Ravendranathan Jefferson C. Frisbee Krishna K. Singh |
| author_facet | Shuhan Bu Aman Singh Hien C. Nguyen Bharatsinai Peddi Kriti Bhatt Naresh Ravendranathan Jefferson C. Frisbee Krishna K. Singh |
| author_sort | Shuhan Bu |
| collection | DOAJ |
| description | Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of <i>protein disulfide isomerase 4</i> (<i>PDIA-4</i>); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFβ-signaling, and inhibition of TGFβ-signaling suppressed EndMT in <i>PDIA-4</i>-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions. |
| first_indexed | 2024-04-24T10:43:54Z |
| format | Article |
| id | doaj.art-ebd1ce516ef14a308ce2ba6bb1dc0840 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:43:54Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ebd1ce516ef14a308ce2ba6bb1dc08402024-04-12T13:20:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257391310.3390/ijms25073913Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and SurvivalShuhan Bu0Aman Singh1Hien C. Nguyen2Bharatsinai Peddi3Kriti Bhatt4Naresh Ravendranathan5Jefferson C. Frisbee6Krishna K. Singh7Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaDepartment of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St. N., London, ON N6A 3K7, CanadaEndothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of <i>protein disulfide isomerase 4</i> (<i>PDIA-4</i>); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFβ-signaling, and inhibition of TGFβ-signaling suppressed EndMT in <i>PDIA-4</i>-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.https://www.mdpi.com/1422-0067/25/7/3913PDIA-4autophagyapoptosisendothelial-to-mesenchymal transitionendothelial functioncardiovascular diseases |
| spellingShingle | Shuhan Bu Aman Singh Hien C. Nguyen Bharatsinai Peddi Kriti Bhatt Naresh Ravendranathan Jefferson C. Frisbee Krishna K. Singh Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival International Journal of Molecular Sciences PDIA-4 autophagy apoptosis endothelial-to-mesenchymal transition endothelial function cardiovascular diseases |
| title | Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival |
| title_full | Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival |
| title_fullStr | Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival |
| title_full_unstemmed | Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival |
| title_short | Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival |
| title_sort | protein disulfide isomerase 4 is an essential regulator of endothelial function and survival |
| topic | PDIA-4 autophagy apoptosis endothelial-to-mesenchymal transition endothelial function cardiovascular diseases |
| url | https://www.mdpi.com/1422-0067/25/7/3913 |
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