TY - JOUR
T1 - Maternal obesity impairs fetal cardiomyocyte contractile function in sheep
AU - Wang, Qiurong
AU - Zhu, Chaoqun
AU - Sun, Mingming
AU - Maimaiti, Rexiati
AU - Ford, Stephen P.
AU - Nathanielsz, Peter W.
AU - Ren, Jun
AU - Guo, Wei
N1 - Funding Information:
The authors thank Dr. John F. Odhiambo, Dr. Adel Ghnenis, Dr. Shuyi Wang, Dr. Guorong Ruan, Dr. Zhilong Chen, Christopher Pankey, Dallas Sturdevant, and Ashley Smith (all from the University of Wyoming) for performing tissue collection and sheep necropsy; and Pan Chen (University of Wyoming) for help in obtaining immunofluorescence microscopic images of fetal sheep LV sections. The authors dedicate this work to the late Stephen P. Ford, M.D., a cofounder of the University of Wyoming Fetal Programming Center. This work was supported by National Institutes of Health (NIH), National Institute of General Medical Sciences Grant GMSP20GM103432; American Heart Association, Beginning Grant-in-Aid award to 16BGIA27790136 (to W.G.); a U.S. Department of Agriculture, National Institute of Food and Agriculture Hatch Project 1009266 (to WG); NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant 1R01HD070096-01A1 (to S.P.F. and P.W.N.). The authors declare no conflicts of interest.
Publisher Copyright:
© 2019 FASEB.
PY - 2019
Y1 - 2019
N2 - Obesity is a major public health problem worldwide. In the United States, one-third of women of reproductive age are obese. Human studies show that maternal obesity (MO) predisposes offspring to cardiovascular disease. However, the underlying mechanisms remain unclear. Given the similarities between pregnancy in sheep and humans,we studied sheep to examine the impact ofMOon fetal cardiomyocyte contractility at term. We observedthatMOimpaired cardiomyocyte contractilityby reducing peak shortening andshortening/relengthening velocity, prolonging time to relengthening. MO disrupted Ca2+ homeostasis in fetal cardiomyocytes, increasing intracellular Ca2+ and inducing cellular Ca2+ insensitivity. The Ca2+-release channelwas impaired, but Ca2+ uptake was unaffected byMO. The upstreamkinases that phosphorylate the Ca2+-release channel-ryanodine receptor-2, PKA, and calmodulin-dependent protein kinase II-were activated in MO fetuses. Contractile dysfunction was associated with an increased ratio of myosin heavy chain (MHC)-b to MHC-a and upregulated cardiac troponin (cTn)-T and tropomyosin, as well as cTn-I phosphorylation. In summary, this is the first characterization of the effects of MO on fetal cardiomyocyte contractility. Our findings indicate that MO impairs fetal cardiomyocyte contractility through altered intracellular Ca2+ handling, overloading fetal cardiomyocyte intracellular Ca2+ and aberrantmyofilament protein composition. Thesemechanisms may contribute to developmental programming by MOof offspring cardiac function and predisposition to later life cardiovascular disease in the offspring.
AB - Obesity is a major public health problem worldwide. In the United States, one-third of women of reproductive age are obese. Human studies show that maternal obesity (MO) predisposes offspring to cardiovascular disease. However, the underlying mechanisms remain unclear. Given the similarities between pregnancy in sheep and humans,we studied sheep to examine the impact ofMOon fetal cardiomyocyte contractility at term. We observedthatMOimpaired cardiomyocyte contractilityby reducing peak shortening andshortening/relengthening velocity, prolonging time to relengthening. MO disrupted Ca2+ homeostasis in fetal cardiomyocytes, increasing intracellular Ca2+ and inducing cellular Ca2+ insensitivity. The Ca2+-release channelwas impaired, but Ca2+ uptake was unaffected byMO. The upstreamkinases that phosphorylate the Ca2+-release channel-ryanodine receptor-2, PKA, and calmodulin-dependent protein kinase II-were activated in MO fetuses. Contractile dysfunction was associated with an increased ratio of myosin heavy chain (MHC)-b to MHC-a and upregulated cardiac troponin (cTn)-T and tropomyosin, as well as cTn-I phosphorylation. In summary, this is the first characterization of the effects of MO on fetal cardiomyocyte contractility. Our findings indicate that MO impairs fetal cardiomyocyte contractility through altered intracellular Ca2+ handling, overloading fetal cardiomyocyte intracellular Ca2+ and aberrantmyofilament protein composition. Thesemechanisms may contribute to developmental programming by MOof offspring cardiac function and predisposition to later life cardiovascular disease in the offspring.
KW - Ca sensitivity
KW - Cardiac programming
KW - Myofilament
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U2 - 10.1096/fj.201800988R
DO - 10.1096/fj.201800988R
M3 - Article
C2 - 30289749
AN - SCOPUS:85061055576
VL - 33
SP - 2587
EP - 2598
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 2
ER -