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NOTCH1 and UPR signaling in embryonic heart development under maternal high-fat diet influence
Yupeng Shi1,2, Bingyu Li2,3, Qingyun Shi1,2
1Department of Obstetrics, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Insights
Maternal high-fat diet (HFD) before and during pregnancy disrupts embryonic heart development by activating the unfolded protein response (UPR) pathway. This leads to suppressed NOTCH1 expression and increased apoptosis, highlighting the need for a balanced maternal diet.
Area of Science:
- Developmental Biology
- Cardiovascular Biology
- Metabolic Disorders
Background:
- Maternal nutrition significantly influences embryonic development.
- High-fat diets (HFD) are increasingly prevalent and linked to adverse health outcomes.
- The impact of maternal HFD on embryonic heart development requires further investigation.
Purpose of the Study:
- To investigate the effects of maternal HFD before and during pregnancy on embryonic heart development.
- To elucidate the molecular mechanisms underlying HFD-induced cardiac abnormalities in embryos.
Main Methods:
- Mice were fed HFD before and during pregnancy.
- Maternal serum lipid profiles were analyzed.
- Embryonic hearts were assessed via H&E staining and Western blot for NOTCH1 and UPR-related proteins.
- Cardiomyocytes were cultured to assess NOTCH1 expression following IRE1α pathway inhibition.
Main Results:
- Maternal HFD increased serum TC, TG, and LDL-C, while decreasing HDL-C.
- Embryonic hearts showed ventricular defects, including abnormal compaction, thinning, and valve issues, with severity correlating to HFD duration.
- NOTCH1 expression was reduced, while UPR markers (XBP1s) and apoptosis (caspase-3/7) were elevated in embryonic ventricular tissues.
- IRE1α pathway inhibition normalized NOTCH1 expression in cultured cardiomyocytes.
Conclusions:
- Maternal HFD before and during pregnancy induces embryonic cardiac developmental abnormalities.
- The IRE1α pathway activation in the unfolded protein response (UPR) appears to mediate these effects by suppressing NOTCH1 and promoting apoptosis.
- Maintaining a balanced maternal diet is crucial for ensuring proper embryonic heart development.
Introduction:
During the submission and review period, I obtained my Master's degree from Beijing Obstetrics and Gynecology Hospital, Capital Medical University, and subsequently joined the Obstetrics Department of the same hospital. Due to this change in status from student to hospital staff, I am now required to use my staff email for correspondence, which has been updated in the manuscript. In addition, our hospital has revised the official format of the institution's name for submissions, and accordingly, the affiliation in the manuscript has been updated from "Beijing Obstetrics and Gynecology Hospital, Capital Medical University" to "Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital." We apologize for any inconvenience these changes may have caused to the editorial team.
Objective:
This study aimed to investigate how maternal high-fat diet (HFD) during pregnancy affects embryonic heart development.
Methods:
C57BL/6J female mice were fed a HFD before and during pregnancy. Maternal blood was collected at P5.5, P10.5, and P14.5 to assess lipid levels. Embryonic hearts at E14.5 were examined by H&E staining, and ventricular protein expression of NOTCH1 and UPR-related molecules was measured via Western blot. E14.5 cardiomyocytes were cultured to evaluate NOTCH1 expression after IRE1α pathway inhibition.
Results:
Compared with the control group (Group A), serum levels of TC, TG, and LDL-C were increased, and HDL-C was decreased in maternal mice fed a high-fat diet during pregnancy (Group B) and a high-fat diet both before and during pregnancy (Group C). Group B embryos exhibited abnormal ventricular wall compaction, thinning, and valve defects, which were more severe in Group C. NOTCH1 expression was reduced in B and C ventricular tissues, while XBP1s and apoptosis-related proteins caspase-3/7 were elevated. Inhibition of the IRE1α pathway abolished differences in NOTCH1 expression among groups in cultured cardiomyocytes.
Conclusion:
Maternal HFD before and during pregnancy induces abnormal embryonic heart development, likely via IRE1α pathway activation in the UPR, which suppresses NOTCH1 expression and promotes apoptosis. These findings underscore the importance of a balanced maternal diet for proper embryonic heart development.
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