1,25-vitamin D3 promotes cardiac differentiation through modulation of the WNT signaling pathway

Abstract

Cardiovascular disease (CV) remains the leading cause of death worldwide. Low levels of vitamin D are associated with high risk of myocardial infarction, even after controlling for factors associated with coronary artery disease. A growing body of evidence suggests that vitamin D plays an important role in CV related signaling pathways. However, little is known about the molecular mechanism by which vitamin D modulates cardiac development. The Wnt signaling pathway plays a pivotal role in tissue development by controlling stem cell renewal, lineage selection and even more importantly heart development. In this study, we examined the role of 1,25-D 3 (active form of vitamin D) on cardiomyocyte proliferation, apoptosis, cell phenotype, cell cycle progression and differentiation into cardiomyotubes. We determined that the addition of 1,25-D 3 to cardiomyocytes cells: 1) Inhibits cell proliferation without promoting apoptosis; 2) Decreases expression of genes related to the regulation of the cell cycle; 3) Promotes cardiomyotubes formation; 4) Induces the expression of Casein kinase-1-α1, a negative regulator of the canonical Wnt signaling pathway; and 5) Increases the expression of the noncanonical Wnt11, which it has been demonstrated to induce cardiac differentiation during embryonic development in adult cells. In conclusion, we postulate that vitamin D promotes cardiac differentiation through a negative modulation of the canonical Wnt signaling pathway and by upregulating the expression of Wnt11. These results suggest that vitamin D repletion to prevent and/or improve cardiovascular disorders that are linked to abnormal cardiac differentiation, such as post infarction cardiac remodeling, deserve further study.

Vitamin D Sufficiency Enhances Differentiation of Patient-Derived Prostate Epithelial Organoids

“…Consistent with the hypothesis, there was enrichment for "Differentiation of Epithelial Tissue" at both time points with sufficient 1,25D (Supplemental Figure S6, red box). The Wnt pathway was selected for additional investigation in the primary prostate cells because previous studies in the RWPE1 prostate cell line, gut, skin and heart have shown 1,25D inhibition of canonical Wnt signaling (Aguilera et al, 2007;Hlaing et al, 2014;Kovalenko et al, 2010;Larriba et al, 2011;Muralidhar et al, 2019).…”

“…Genes regulated by vitamin D are involved in proliferation, differentiation, and apoptosis pathways (Feldman et al, 2014). Vitamin D metabolites are pro-differentiating in a variety of cell and tissue types, including keratinocytes (MacLaughlin et al, 1990), intestinal villi (Peregrina et al, 2015;Spielvogel et al, 1972), cardiomyocytes (Hlaing et al, 2014), odontoblasts (Mucuk et al, 2017), placenta (Hutabarat et al, 2018), and macrophages (Abe et al, 1981;James et al, 1997). While some of these studies explore 1,25D action in benign cells, the majority of reports focus on vitamin D inhibition of cancer cell growth and tumor progression (Aguilera et al, 2007;Banks and Holick, 2015;Holick et al, 2007;Larriba et al, 2011;Tavera-Mendoza et al, 2017;Yang et al, 2017), and very little is known about the pro-differentiating activity of vitamin D in benign prostate.…”