Abstract 20627: Defective Vitamin D Signaling is Associated With Profound Calcium Handling Abnormalities, Activation of Protein Kinase C Signaling
Vitamin D deficiency is associated with the development of cardiac dysfunction, but the pathogenic mechanism is not known. Here, we examine the relationship between defective vitamin D signaling and the development of cardiac hypertrophy in vivo.
Method and Results: We analyzed vitamin D receptor knockout (VDR KO) mice, which lack the VDRs that are essential for mediating vitamin D signaling. VDR KO mice showed modest cardiac hypertrophy at baseline (15%). Induction of pressure overload by transverse aortic constriction (TAC) resulted in significant increases in heart weight/tibial length (HW/TL) and lung weight/TL ratios in both wild-type (WT) and VDR KO mice at 4 weeks, with a greater increase in HW/TL ratio in VDR KO mice (p<0.05). VDR KO mice also showed significant increases in atrial natriuretic factor tissue mRNA (41%), beta-myosin heavy chain tissue mRNA (320%), and serum brain natriuretic peptide (20%) levels (p<0.05 for all) compared to WT after TAC. Analysis of calcium handing demonstrated that VDR KO cardiomyocytes (CM) showed profound Ca2+ handling abnormalities compared with the WT CM as shown by significantly decreased Fura-2 ratios (F340/380)(15%), which represent changes in intracellular Ca2+ concentrations; decreased systolic % peak Ca2+ measured as Fura-2 ratios (36.5%); decreased index of Ca2+ reuptake measured as Ca2+ time to 50% relaxation (25%); and impaired time constant of decay t (tau) (7%)(p<0.05 for all parameters). We also found the expression of two classical protein kinase C (PKC) isoforms, alpha and beta, which have Ca2+-dependent activation and are implicated in cardiac hypertrophy, were significantly increased in VDR KO mice at baseline. In contrast, the expression of other novel or atypical PKC isoforms, PKC epsilon and PKC zeta, were unchanged.
Conclusions: Defective vitamin D signaling is associated with profound Ca2+ handling defects and activation of classic PKC isoforms, and leads to exaggerated cardiac hypertrophy in response to TAC.
- © 2010 by American Heart Association, Inc.