title: 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-D3 to 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 noncanonical WNT11, 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 of WNT11. 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.
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Su M
authors.initials: SM
authors.lastname: Hlaing
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Garcia
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Jaime R
authors.initials: JR
authors.lastname: Contreras
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Norris
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Monica G
authors.initials: MG
authors.lastname: Ferrini
authors.affiliation: Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA Departments of Internal MedicineHealth and Life SciencesDivision of EndocrinologyMetabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USADepartment of MedicineDavid Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA joartaza@ucla.edu.
authors.forename: Jorge N
authors.initials: JN
authors.lastname: Artaza
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000494:pharmacology*; D004622:Embryo, Mammalian; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol
keywords: APC; Csnk1α1; Gsk3β; VDR; Wnt11; β-catenin