2. Academic Validation
  3. Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification

  • Circulation. 2024 Feb 13. doi: 10.1161/CIRCULATIONAHA.123.065830.
Xiaoxuan Zhai # 1 2 3,  Shengchuan Cao # 1 2 3,  Jiali Wang 1 2 3 4,  Bao Qiao 1 2 3 4,  Xuehao Liu 1 2 3 4,  Rui Hua 1 2 3 4,  Menglin Zhao 1 2 3 4,  Shukun Sun 1 2 3 4,  Yu Han 1 2 3 4,  Shuo Wu 1 2 3,  Jiaojiao Pang 1 2 3 4,  Qiuhuan Yuan 1 2 3 4,  Bailu Wang 5,  Feng Xu 1 2 3,  Shujian Wei 1 2 3,  Yuguo Chen 1 2 3
Affiliations

Affiliations

  • 1 Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.).
  • 2 Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.).
  • 3 Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.).
  • 4 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.).
  • 5 National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Clinical Trial Center, Qilu Hospital of Shandong University, Jinan, China (B.W.).
  • # Contributed equally.
PMID: 38348663 DOI: 10.1161/CIRCULATIONAHA.123.065830
Abstract

Background: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated.

Methods: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing β-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms.

Results: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2.

Conclusions: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

Keywords

4-hydroxynonenal; Runx2; aldehyde dehydrogenase 2; carbonylation; vascular calcification.

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