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EFFECTS OF VITAMIND D PERTURBATION ON CARDIAC IRON
OVERLOAD
by
Maya Otto-Duessel
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNTVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(SYSTEMS BIOLOGY AND DISEASE)
December 2010
Copyright 2010 Maya Otto-Duessel
Object Description
| Title | Effects of vitamin D perturbation on cardiac iron overload |
| Author | Otto-Duessel, Maya |
| Author email | motto-duessel@chla.usc.edu; mayaottoduessel@hotmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology & Disease |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-11-08 |
| Advisor (committee chair) | Wood, John |
| Advisor (committee member) |
Farley, Robert Meiselman, Herbert Coates, Thomas McDonough, Alicia |
| Abstract | Iron mediated cardiomyopathy remains the leading cause of mortality in β-thalassemia patients. Cardiac iron accumulates in the first and second decade of life and it is difficult to remove. Thus, treatment options to prevent cardiac iron uptake are much needed.; Recently, vitamin D deficiency has been associated with increased cardiac iron overload in β-thalassemia patients. In these patients, PTH and 1-25-(OH)2-D are elevated. Both PTH and 1-25-OH-D levels upregulate L-type voltage gated calcium channels (LVGCC), in vitro. LVGCCs have also been proposed to be the dominant mechanism for iron influx into cardiomyocytes in mice. Therefore, we hypothesized that vitamin D deficiency increases cardiac iron uptake via LVGCC up-regulation by PTH and 1-25(OH)2-D.; We created vitamin D deficiency in a murine hemochromatosis model in order to understand possible contributing mechanisms. Verapamil decreased cardiac iron consistent with LVGCC involvement. Furthermore, we observed a strong correlation between cardiac and calcium iron stores (R²=0.63). However, large perturbations of the vitamin D axis failed to modulate either cardiac iron or cardiac calcium, contrary to our initial hypothesis. Since verapamil also unexpectedly lowered hepatic iron, we sought an alternate means of LVGCC manipulation. LVGCCs are also modulated by the autonomic nervous system via L-type current changes. Therefore, positive and negative inotropic interventions should impact cardiac iron levels. As predicted, β-blockade lowered cardiac calcium (55%, p=0.021) and iron content (55%, p=0.011). Surprisingly isoproterenol reduced cardiac iron content the most (58%, p<0.001) without lowering calcium content, must likely through recruitment of T-type calcium transporters. While isoproterenol has many undesirable side effects, β- blockers may be a safe, affordable treatment option to protect thalassemia major patients. |
| Keyword | beta-thalassemia; iron overload; cardiomyopathy; vitamin D axis |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3523 |
| Rights | Otto-Duessel, Maya |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-OttoDuessel-4199 |
| Archival file | uscthesesreloadpub_Volume26/etd-OttoDuessel-4199.pdf |
Description
| Title | Page 1 |
| Full text | EFFECTS OF VITAMIND D PERTURBATION ON CARDIAC IRON OVERLOAD by Maya Otto-Duessel A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNTVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (SYSTEMS BIOLOGY AND DISEASE) December 2010 Copyright 2010 Maya Otto-Duessel |
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