Novel Small Leucine-Rich Repeat Protein Podocan Is a Negative Regulator of Migration and Proliferation of Smooth Muscle Cells, Modulates Neointima Formation, and Is Expressed in Human Atheroma

Abstract

Background SMC migration and proliferation critically influence the clinical course of vascular disease. We tested the effect of the novel small leucine-rich repeat protein podocan on SMC migration and proliferation using a podocan deficient mouse in combination with a model of arterial injury and aortic explant SMC culture. In addition, we examined the effect of overexpression of the human form of podocan on human SMC and tested for podocan expression in human atherosclerosis. In all these conditions we evaluated concomitantly the Wnt-TCF-pathway. Methods and Results Podocan was strongly and selectively expressed in arteries of WT mice after injury. Podocan−/− mice showed increased arterial lesion formation as compared to WT littermates in response to injury (P<0.05). Also, SMC proliferation was increased in arteries of podocan −/− mice compared to WT (P<0.05). In vitro, migration and proliferation were increased in podocan−/− SMC and were normalized by transfection with the WT podocan gene (P<0.05). In addition, upregulation of the Wnt-TCF-pathway was found in SMC of podocan−/− mice both in vitro and in vivo. On the other hand, podocan overexpression in human SMC significantly reduced SMC migration and proliferation inhibiting the Wnt-TCF-pathway. Podocan and a Wnt-TCF-pathway marker were differently expressed in human coronary restenotic versus primary lesions. Conclusions Podocan appears to be a potent negative regulator of the migration and proliferation of both murine and human SMC. The lack of podocan results in excessive arterial repair and prolonged SMC proliferation, which likely is mediated by the Wnt-TCF-pathway.

Development and Validation of a Prognostic Nomogram for Gastric Cancer Based on DNA Methylation-Driven Differentially Expressed Genes

“…ECM molecules are highly effective modulators of cell functions, such as migration and proliferation [32]. Given the inhibitory effect of high podocan levels on smooth muscle cell (SMC) proliferation [33], PODN may also be involved in cell proliferation regulation, which requires further experimental validation. Ras homolog family member J (RHOJ), a member of the Rho GTPase family, acts as a molecular switch by regulating cell functions, such as migration and proliferation, correlating well with increased cell motility and invasiveness [34].…”

Proteoglycan form and function: A comprehensive nomenclature of proteoglycans

“…In normal kidneys, podocan shows a distribution along the basement membrane of the glomeruli and proximal tubules [ 604 ], and more recent studies have shown that podocan is a constituent of human aortic tissue [ 607 ]. In agreement with its tissue distribution, podocan has been identified as a negative regulator of migration and proliferation of smooth muscle cells [ 608 ]. On this basis, podocan can affect atherosclerosis development like other SLRPs, such as biglycan.…”

“…On this basis, podocan can affect atherosclerosis development like other SLRPs, such as biglycan. Of note, Podn −/− smooth muscle cells exhibit a constitutively-activated Wnt pathway, whereas wild-type smooth muscle cells overexpressing podocan have a significantly depressed Wnt signaling pathway [ 608 ], biological properties also shared by other SLRPs (see above). As in the case of other-non canonical SLRPs, podocan shares functional properties with decorin and biglycan, especially in its ability to bind collagen I and to induce p21 WAF1 and growth suppression [ 605 ].…”

Podocan Is Expressed in Blood and Adipose Tissue and Correlates Negatively With the Induction of Diabetic Nephropathy

“…In fact, podocan is strongly and selectively expressed in the arteries of wild-type mice after injury. Podocan-deficient mice show increased arterial lesion formation in response to injury compared with their wild-type littermates [ 4 – 6 ]. In addition, the podocan-deficient mice are characterized by an increase in SMC proliferation, and this effect is exerted through the activation of the Wnt- β -catenin pathway in the SMCs both in vitro and in vivo [ 6 ].…”