Why the study?
Hyperoxia causes diastolic dysfunction and suppresses fatty acid synthesis genes required for atrial cardiomyocyte proliferation and survival, but the underlying signaling mechanisms were unclear.
Does inhibiting PPARγ signaling improve proliferation and survival of atrial cardiomyocytes in neonatal mice exposed to hyperoxia?
Does inhibiting PPARγ signaling improve proliferation and survival of atrial cardiomyocytes in neonatal mice exposed to hyperoxia?
Inhibiting PPARγ signaling restores atrial cardiomyocyte proliferation and survival in hyperoxia-exposed neonatal mice, suggesting a potential therapeutic target for preventing diastolic dysfunction in preterm infants.
May identify PPARγ inhibition as a target in hyperoxia-exposed neonates; leaves open translation to prevent diastolic dysfunction in preterm infants.
Diastolic dysfunction is increasingly common in preterm infants exposed to supplemental oxygen (hyperoxia). Previous studies in neonatal mice showed hyperoxia suppresses fatty acid synthesis genes required for proliferation and survival of atrial cardiomyocytes. The loss of atrial cardiomyocytes creates a hypoplastic left atrium that inappropriately fills the left ventricle during diastole. Here, we show that hyperoxia stimulates adenosine monophosphate-activated kinase (AMPK) and peroxisome proliferator activated receptor-gamma (PPARγ) signaling in atrial cardiomyocytes. While both pathways can regulate lipid homeostasis, PPARγ was the primary pathway by which hyperoxia inhibits fatty acid gene expression and inhibits proliferation of mouse atrial HL-1 cells. It also enhanced the toxicity of hyperoxia by increasing expression of activating transcription factor (ATF) 5 and other mitochondrial stress response genes. Silencing PPARγ signaling restored proliferation and survival of HL-1 cells as well as atrial cardiomyocytes in neonatal mice exposed to hyperoxia. Our findings reveal PPARγ enhances the toxicity of hyperoxia on atrial cardiomyocytes, thus suggesting inhibitors of PPARγ signaling may prevent diastolic dysfunction in preterm infants. Hyperoxia activated AMPK and PPARγ in the atria of newborn mice and HL-1 atrial cardiomyocytes. While activating AMPK with AICAR mimicked the effects of hyperoxia on fatty acid (FA) synthesis, proliferation, and survival in room air, silencing AMPK did not restore these functions in hyperoxia. Hyperoxia may therefore indirectly activated AMPK when it suppressed SCD1, a known AMPK inhibitor. Inhibiting PPARγ increased FA synthesis, proliferation, and survival and reduced the mitochondrial unfolded protein response (mitoUPR) in hyperoxia exposed cells and mice. • Hyperoxia inhibits fatty acid synthesis genes and expansion of atrial cardiomyocytes. • Hyperoxia activates two key regulators of lipid metabolism AMPK and PPARγ. • Silencing PPARγ but not AMPK increases fatty acid synthesis and expansion of HL-1 atrial cardiomyocytes in hyperoxia. • PPARγ inhibition restores atrial cardiomyocyte proliferation and survival in mice exposed to hyperoxia.
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Cohen et al. (2024) studied this question.
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