T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice

Objectives: Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe 2+ uptake in thalassemic cardiomyocytes are mainly medi...

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Main Authors: Kumfu S., Chattipakorn S., Chinda K., Fucharoen S., Chattipakorn N.
Format: Article
Language:English
Published: 2014
Online Access:http://www.ncbi.nlm.nih.gov/pubmed/22404220
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spelling th-cmuir.6653943832-10752014-08-29T09:17:43Z T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice Kumfu S. Chattipakorn S. Chinda K. Fucharoen S. Chattipakorn N. Objectives: Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe 2+ uptake in thalassemic cardiomyocytes are mainly mediated by T-type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L-type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron-overload condition has not been investigated. Methods: An iron-overload condition was induced in genetically altered β-thalassemic mice and adult wild-type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1month with continuous iron feeding. Results: Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non-transferrin-bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron-overloaded thalassemic mice. Conclusions: DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron-overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron-overloaded mice. © 2012 John Wiley & Sons A/S. 2014-08-29T09:17:43Z 2014-08-29T09:17:43Z 2012 Article 9024441 10.1111/j.1600-0609.2012.01779.x 22404220 EJHAE http://www.ncbi.nlm.nih.gov/pubmed/22404220 http://www.scopus.com/inward/record.url?eid=2-s2.0-84861187773&partnerID=40&md5=78f28a0e653c58cc846780452cd70ea0 http://cmuir.cmu.ac.th/handle/6653943832/1075 English
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
language English
description Objectives: Iron-overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe 2+ uptake in thalassemic cardiomyocytes are mainly mediated by T-type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L-type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron-overload condition has not been investigated. Methods: An iron-overload condition was induced in genetically altered β-thalassemic mice and adult wild-type mice by feeding them with an iron diet (0.2% ferrocene w/w) for 3months. Then, blockers for LTCC (verapamil and nifedipine), TTCC (efonidipine), and DMT1 (ebselen) as well as iron chelator desferoxamine (DFO) were given for 1month with continuous iron feeding. Results: Treatment with LTCC, TTCC, DMT1 blockers, and DFO reduced cardiac iron deposit, cardiac malondialdehyde (MDA), plasma non-transferrin-bound iron, and improved heart rate variability and left ventricular (LV) function in thalassemic mice with iron overload. Only TTCC and DMT1 blockers and DFO reduced liver iron accumulation, liver MDA, plasma MDA, and decreased mortality rate in iron-overloaded thalassemic mice. Conclusions: DMT1, LTCC, and TTCC played important roles for iron entry in the thalassemic heart under an iron-overloaded condition. Unlike LTCC blocker, TTCC blocker provided all benefits including attenuating iron deposit in both the heart and liver, reduced oxidative stress, and decreased mortality in iron-overloaded mice. © 2012 John Wiley & Sons A/S.
format Article
author Kumfu S.
Chattipakorn S.
Chinda K.
Fucharoen S.
Chattipakorn N.
spellingShingle Kumfu S.
Chattipakorn S.
Chinda K.
Fucharoen S.
Chattipakorn N.
T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
author_facet Kumfu S.
Chattipakorn S.
Chinda K.
Fucharoen S.
Chattipakorn N.
author_sort Kumfu S.
title T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
title_short T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
title_full T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
title_fullStr T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
title_full_unstemmed T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
title_sort t-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice
publishDate 2014
url http://www.ncbi.nlm.nih.gov/pubmed/22404220
http://www.scopus.com/inward/record.url?eid=2-s2.0-84861187773&partnerID=40&md5=78f28a0e653c58cc846780452cd70ea0
http://cmuir.cmu.ac.th/handle/6653943832/1075
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