PMID- 38454645 OWN - NLM STAT- MEDLINE DCOM- 20240507 LR - 20240514 IS - 1755-3245 (Electronic) IS - 0008-6363 (Print) IS - 0008-6363 (Linking) VI - 120 IP - 6 DP - 2024 May 7 TI - Smooth muscle cell-specific matrix metalloproteinase 3 deletion reduces osteogenic transformation and medial artery calcification. PG - 658-670 LID - 10.1093/cvr/cvae035 [doi] AB - AIMS: Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification. METHODS AND RESULTS: We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries in patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process. CONCLUSION: These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD. CI - (c) The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact journals.permissions@oup.com. FAU - Xie, Yangzhouyun AU - Xie Y AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA. FAU - Lin, Tonghui AU - Lin T AD - Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA. FAU - Jin, Ying AU - Jin Y AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA. FAU - Berezowitz, Alexa G AU - Berezowitz AG AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA. FAU - Wang, Xue-Lin AU - Wang XL AD - Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA. FAU - Lu, Jinny AU - Lu J AD - Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA. FAU - Cai, Yujun AU - Cai Y AUID- ORCID: 0000-0002-0323-6700 AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA. AD - Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA. FAU - Guzman, Raul J AU - Guzman RJ AUID- ORCID: 0000-0002-7567-9930 AD - Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA. AD - Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA. LA - eng GR - R01 HL138357/HL/NHLBI NIH HHS/United States GR - R01 HL157111/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Cardiovasc Res JT - Cardiovascular research JID - 0077427 SB - IM CIN - Cardiovasc Res. 2024 May 7;120(6):565-566. PMID: 38630897 MH - Mice MH - Mice, Inbred C57BL MH - Rats MH - Rats, Sprague-Dawley MH - *Matrix Metalloproteinase 3/deficiency/genetics/metabolism MH - *Gene Deletion MH - *Vascular Calcification/enzymology/genetics MH - Disease Models, Animal MH - Muscle, Smooth, Vascular/cytology MH - Humans MH - Recombinant Proteins/pharmacology MH - Aorta/metabolism MH - Gene Expression PMC - PMC11074797 OTO - NOTNLM OT - Calcification OT - MMP-3 OT - Osteogenic transformation OT - Smooth muscle cells COIS- Conflict of interest: None declared. EDAT- 2024/03/08 06:43 MHDA- 2024/05/07 06:42 PMCR- 2025/03/08 CRDT- 2024/03/08 02:12 PHST- 2023/03/11 00:00 [received] PHST- 2023/11/30 00:00 [revised] PHST- 2023/12/12 00:00 [accepted] PHST- 2025/03/08 00:00 [pmc-release] PHST- 2024/05/07 06:42 [medline] PHST- 2024/03/08 06:43 [pubmed] PHST- 2024/03/08 02:12 [entrez] AID - 7624232 [pii] AID - cvae035 [pii] AID - 10.1093/cvr/cvae035 [doi] PST - ppublish SO - Cardiovasc Res. 2024 May 7;120(6):658-670. doi: 10.1093/cvr/cvae035.