Cardiac specific ATP-sensitive K+ channel (KATP) overexpression results in embryonic lethality.
Transgenic mice overexpressing SUR1 and gain of function Kir6.2[∆N30, K185Q] K(ATP) channel subunits, under cardiac α-myosin heavy chain (αMHC) 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 α smooth muscle actin (αSMA) 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.
Department of Pediatrics, St. Louis, MO, 63110, USA. amir.toib@drexelmed.edu
Amir
A
Toib
Hai Xia
HX
Zhang
Thomas J
TJ
Broekelmann
Krzysztof L
KL
Hyrc
Qiusha
Q
Guo
Feng
F
Chen
Maria S
MS
Remedi
Colin G
CG
Nichols
D000818:Animals; D020964:Embryo Loss / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005804:Genes, Lethal; D006321:Heart / Q000503:physiopathology; D006325:Heart Atria / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D054086:KATP Channels / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D011247:Pregnancy
D054086:KATP Channels