| First Author | Zhu L | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 51 | Pages | 19465-19474 |
| PubMed ID | 31628194 | Mgi Jnum | J:282865 |
| Mgi Id | MGI:6383768 | Doi | 10.1074/jbc.RA119.009758 |
| Citation | Zhu L, et al. (2019) Hyperhomocysteinemia induces vascular calcification by activating the transcription factor RUNX2 via Kruppel-like factor 4 up-regulation in mice. J Biol Chem 294(51):19465-19474 |
| abstractText | One of the main characteristics of atherosclerosis is vascular calcification, which is linked to adverse cardiovascular events. Increased homocysteine (Hcy), a feature of hyperhomocysteinemia, is correlated with advanced vascular calcification and phenotypic switching of vascular smooth muscle cells (VSMCs). Oxidative stress and high phosphate levels also induce VSMC calcification, suggesting that the Kruppel-like factor 4 (KLF4) signaling pathway may also contribute to vascular calcification. In this study, we investigated this possibility and the role and mechanisms of Hcy in vascular calcification. We found that in atherosclerotic apolipoprotein E-deficient (ApoE(-/-)) mice, Hcy significantly increases vascular calcification in vivo, as well as VSMC calcification in vitro Of note, the Hcy-induced VSMC calcification was correlated with elevated KLF4 levels. Hcy promoted KLF4 expression in calcified atherosclerotic lesions in vivo and in calcified VSMCs in vitro shRNA-mediated KLF4 knockdown blocked the Hcy-induced up-regulation of runt-related transcription factor 2 (RUNX2) and VSMC calcification. RUNX2 inhibition abolished Hcy-induced VSMC calcification. Using ChIP analysis, we demonstrate that KLF4 interacts with RUNX2, an interaction promoted by Hcy stimulation. Our experiments also revealed that the KLF4 knockdown attenuates Hcy-induced RUNX2 transactivity, indicating that KLF4 is important in modulating RUNX2 transactivity. These findings support a role for Hcy in regulating vascular calcification through a KLF4-RUNX2 interaction and indicate that Hcy-induced, enhanced RUNX2 transactivity increases VSMC calcification. These insights reveal possible opportunities for developing interventions that prevent or manage vascular calcification. |
