The Interplay of WNT and PPARγ Signaling in Vascular Calcification

Abstract

Vascular calcification (VC), the ectopic deposition of calcium phosphate crystals in the vessel wall, is one of the primary contributors to cardiovascular death. The pathology of VC is determined by vascular topography, pre-existing diseases, and our genetic heritage. VC evolves from inflammation, mediated by macrophages, and from the osteochondrogenic transition of vascular smooth muscle cells (VSMC) in the atherosclerotic plaque. This pathologic transition partly resembles endochondral ossification, involving the chronologically ordered activation of the β-catenin-independent and -dependent Wingless and Int-1 (WNT) pathways and the termination of peroxisome proliferator-activated receptor γ (PPARγ) signal transduction. Several atherosclerotic plaque studies confirmed the differential activity of PPARγ and the WNT signaling pathways in VC. Notably, the actively regulated β-catenin-dependent and -independent WNT signals increase the osteochondrogenic transformation of VSMC through the up-regulation of the osteochondrogenic transcription factors SRY-box transcription factor 9 (SOX9) and runt-related transcription factor 2 (RUNX2). In addition, we have reported studies showing that WNT signaling pathways may be antagonized by PPARγ activation via the expression of different families of WNT inhibitors and through its direct interaction with β-catenin. In this review, we summarize the existing knowledge on WNT and PPARγ signaling and their interplay during the osteochondrogenic differentiation of VSMC in VC. Finally, we discuss knowledge gaps on this interplay and its possible clinical impact.

Thyroid Hormone Nuclear Receptor TRα1 and Canonical WNT Pathway Cross-Regulation in Normal Intestine and Cancer

“…It is worth noting that TRb or other nuclear receptors and bcatenin/Tcf (alone or in combination) have been shown to form protein complexes (49)(50)(51)(52). We can speculate that TRa1 interacts with b-catenin/Tcf4 complex on WNT targets and that this process might be independent from T3.…”

Histone Lysine Methylation Modification and Its Role in Vascular Calcification

“…Besides acting on lysine, SET8 also can methylate non-histone proteins such as TWIST and p53 ( 105 ). On the one hand, SET8 binds directly to and inactivates the target gene by monomethylating H4K20, resulting in the inhibition of its downstream pathways in the pathogenesis of some diseases ( 108 ); on the other hand, SET8/H4K20me1 is enriched in the promoter and coding regions of transcriptionally active genes, for example, mediating the transcriptional activation of Wnt target gene ( 109 ), which can regulate the expression of the target protein RUNX2 and, in turn, may regulate the phenotypic transformation of VSMCs ( 110 ). Furthermore, downregulation of SET8-mediated H4K20me1 is involved in the increasing modulation of PTEN expression, which mediates endothelial inflammation to generate VC ( 111 ).…”

The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators

“…Meanwhile, PPARγ prevents the degradation of cyclin-dependent kinase inhibitors (CDKIs) and p27 induced by growth factors, and inhibits the formation of cyclin-dependent kinase complex (Cyclin-CDK), thereby inhibits proliferation, migration, and apoptosis ( Law et al, 2000 ; Fu et al, 2001 ). (5) PPARγ inhibits the expression of MMP-9 and MMP-2 that can decompose collagen and fibers in macrophages ( Luo et al, 2007 ; Reinhold et al, 2020 ), reduces the fragility of the fiber cap and enhances the stability of the plaque. Therefore, the functional regulation of PPARγ is of very important for the prevention and treatment of atherosclerosis.…”