| First Author | Choudhury S | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 9 | Pages | e108382 |
| PubMed ID | 25268137 | Mgi Jnum | J:223110 |
| Mgi Id | MGI:5647970 | Doi | 10.1371/journal.pone.0108382 |
| Citation | Choudhury S, et al. (2014) Abnormal calcium handling and exaggerated cardiac dysfunction in mice with defective vitamin d signaling. PLoS One 9(9):e108382 |
| abstractText | AIM: Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction. METHODS AND RESULTS: We analyzed 1alpha-hydroxylase (1alpha-OHase) knockout (1alpha-OHase-/-) mice, which lack 1alpha-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1alpha-OHase-/- mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1alpha-OHase-/- mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1alpha-OHase-/- mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1alpha-OHase-/- CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1alpha-OHase-/- mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals. CONCLUSIONS: Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1alpha-OHase-/- mice. |
