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

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

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Title: Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling
Author: Choudhury, Sangita; Bae, Soochan; Ke, Qingen; Lee, Ji Yoo; Singh, Sylvia S.; St-Arnaud, René; del Monte, Federica; Kang, Peter M.

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Citation: Choudhury, Sangita, Soochan Bae, Qingen Ke, Ji Yoo Lee, Sylvia S. Singh, René St-Arnaud, Federica del Monte, and Peter M. Kang. 2014. “Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling.” PLoS ONE 9 (9): e108382. doi:10.1371/journal.pone.0108382. http://dx.doi.org/10.1371/journal.pone.0108382.
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Abstract: 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 (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ 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, 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 1α-OHase−/− mice.
Published Version: doi:10.1371/journal.pone.0108382
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182450/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:13347504
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