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

Abstract

Cardiovascular disease (CVD) 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 indicates that vitamin D plays an important role in CVD-related signaling pathways. However, little is known about the molecular mechanism by which vitamin D modulates heart 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-D3(the 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-D3to cardiomyocytes cells: i) inhibits cell proliferation without promoting apoptosis; ii) decreases expression of genes related to the regulation of the cell cycle; iii) promotes formation of cardiomyotubes; iv) induces the expression of casein kinase-1-α1, a negative regulator of the canonical WNT signaling pathway; and v) increases the expression of the noncanonicalWNT11, which it has been demonstrated to induce cardiac differentiation during embryonic development and 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 ofWNT11. These results indicate that vitamin D repletion to prevent and/or improve cardiovascular disorders that are linked with abnormal cardiac differentiation, such as post infarction cardiac remodeling, deserve further study.