title: Abnormal calcium handling and exaggerated cardiac dysfunction in mice with defective vitamin d signaling.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sangita
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ji Yoo
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Singh
authors.affiliation: Shriners Hospital and Departments of Surgery and Human Genetics, McGill University, Montreal, Canada.
authors.forename: René
authors.initials: R
authors.lastname: St-Arnaud
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Federica Del
authors.initials: FD
authors.lastname: Monte
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004872:Ergocalciferols / Q000494:pharmacology; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics*; D014807:Vitamin D / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004872:Ergocalciferols; D014807:Vitamin D; C084656:paricalcitol; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D002118:Calcium