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Journal article
Cardiac specific ATP-sensitive K+ channel (K-ATP) overexpression results in embryonic lethality
Journal of molecular and cellular cardiology, v 53(3), pp 437-445
01 Sep 2012
PMID: 22796573
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Transgenic mice overexpressing SUR1 and gain of function Kir6.2[Delta N30, K185Q] K-ATP channel subunits, under cardiac a-myosin heavy chain (alpha MHC) promoter control, demonstrate arrhythmia susceptibility and premature death. Pregnant mice, crossed to carry double transgenic progeny, which harbor high levels of both overexpressed subunits, exhibit the most extreme phenotype and do not deliver any double transgenic pups. To explore the fetal lethality and embryonic phenotype that result from K-ATP overexpression, wild type (WT) and K-ATP overexpressing embryonic cardiomyocytes were isolated, cultured and voltage-clamped using whole cell and excised patch clamp techniques. Whole mount embryonic imaging, Hematoxylin and Eosin (H&E) and alpha smooth muscle actin (alpha SMA) immunostaining were used to assess anatomy, histology and cardiac development in K-ATP overexpressing and WT embryos. Double transgenic embryos developed in utero heart failure and 100% embryonic lethality by 11.5 days post conception (dpc). K-ATP currents were detectable in both WT and K-ATP-overexpressing embryonic cardiomyocytes, starting at early stages of cardiac development (9.5 dpc). In contrast to adult cardiomyocytes, WT and K-ATP-overexpressing embryonic cardiomyocytes exhibit basal and spontaneous K-ATP current, implying that these channels may be open and active under physiological conditions. At 9.5 dpc, live double transgenic embryos demonstrated normal looping pattern, although all cardiac structures were collapsed, probably representing failed, non-contractile chambers. In conclusion, K-ATP channels are present and active in embryonic myocytes, and overexpression causes in utero heart failure and results in embryonic lethality. These results suggest that the K-ATP channel may have an important physiological role during early cardiac development. (C) 2012 Elsevier Ltd. All rights reserved.
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Details
- Title
- Cardiac specific ATP-sensitive K+ channel (K-ATP) overexpression results in embryonic lethality
- Creators
- Amir Toib - Dept Pediat, St Louis, MO 63110 USAHai Xia Zhang - College Station Medical CenterThomas J. Broekelmann - Saint Louis UniversityKrzysztof L. Hyrc - Washington University in St. LouisQiusha Guo - Saint Louis UniversityFeng Chen - Saint Louis UniversityMaria S. Remedi - Saint Louis UniversityColin G. Nichols - Saint Louis University
- Publication Details
- Journal of molecular and cellular cardiology, v 53(3), pp 437-445
- Publisher
- Elsevier
- Number of pages
- 9
- Grant note
- P30 NS057105; T32 HL07873 / Neuroscience Blueprint Interdisciplinary Center Core Grant HL45742; HL95010 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Children's Discovery Institute at Washington University R01HL045742 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000307861400018
- Scopus ID
- 2-s2.0-84864813430
- Other Identifier
- 991021861635404721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Cardiac & Cardiovascular Systems
- Cell Biology