Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling

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 1α-hydroxylase (1α-OHase) knockout (1α-OHase(−/−)) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase(−/−) mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase(−/−) mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca(2+)) transient demonstrated profound Ca(2+) handling abnormalities in 1α-OHase(−/−) mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D(3) analog, significantly attenuated defective Ca(2+) handling in 1α-OHase(−/−) CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-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, Ca(2+) 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 Ca(2+) handling and defective vitamin D signaling in 1α-OHase(−/−) mice.