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Metabolic Profiles in Ovine Carotid Arteries with Developmental Maturation and Long-Term Hypoxia.

Goyal R, Longo LD - PLoS ONE (2015)

Bottom Line: Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia.LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression.Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America.

ABSTRACT

Background: Long-term hypoxia (LTH) is an important stressor related to health and disease during development. At different time points from fetus to adult, we are exposed to hypoxic stress because of placental insufficiency, high-altitude residence, smoking, chronic anemia, pulmonary, and heart disorders, as well as cancers. Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia. Similarly, prolonged hypoxic exposure during adult life can lead to acute mountain sickness, chronic fatigue, chronic headache, cognitive impairment, acute cerebral and/or pulmonary edema, and death.

Aim: LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression. Importantly, during the intrauterine life, a fetus is under a relative hypoxic environment, as compared to newborn or adult. Thus, the changes in gene expression with development from fetus to newborn to adult may be as a consequence of underlying changes in the metabolic profile because of the hypoxic environment along with developmental maturation. To examine this possibility, we examined the metabolic profile in carotid arteries from near-term fetus, newborn, and adult sheep in both normoxic and long-term hypoxic acclimatized groups.

Results: Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation.

No MeSH data available.


Related in: MedlinePlus

Box plots of the membrane lipid hydrolysis pathway comparing the six study groups.In each diagram are shown from left to right: normoxic and hypoxic fetus; normoxic and hypoxic newborn (NB); and normoxic and hypoxic adult. The Fig also demonstrates an overview of the membrane lipid hydrolysis pathway Upward red arrow means significantly (P < 0.05) higher for the noted comparison. Downward green arrow means significantly (P < 0.05) lower for the noted comparison. Upward and downward arrows together means approach significance (0.05 < P < 0.1). N = 8 in each group.
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pone.0130739.g007: Box plots of the membrane lipid hydrolysis pathway comparing the six study groups.In each diagram are shown from left to right: normoxic and hypoxic fetus; normoxic and hypoxic newborn (NB); and normoxic and hypoxic adult. The Fig also demonstrates an overview of the membrane lipid hydrolysis pathway Upward red arrow means significantly (P < 0.05) higher for the noted comparison. Downward green arrow means significantly (P < 0.05) lower for the noted comparison. Upward and downward arrows together means approach significance (0.05 < P < 0.1). N = 8 in each group.

Mentions: Metabolites indicating the hydrolysis of phosphatidylcholines, phosphatidylglycerol [56], and phosphatidylinositol-1-phosphate—namely, glycerophosphocholine (GPC), glycerol-2-phosphate (G2P), and inositol-1-phosphate (I1P)—were elevated in at least one of the age groups acclimated to high altitude relative to their normoxic controls (Fig 7). Glycerol-3-phosphate (G3P), choline phosphate, and phosphoethanolamine, which are potential markers of phospholipid degradation but also can serve as substrates for phospholipid synthesis, also were elevated in the hypoxic newborn carotid arteries. A range of lysophospholipids containing an acyl group at the sn-1 position on the glycerol backbone—for example 1-palmitoylglycerophosphocholine and 1-stearolyglycerophosphoserine—were decreased in the LTH acclimatized newborns, and, to a lesser extent in the fetuses. Lysolipids with the sn-1 configuration are the products of phospholipase A2 (PLA2) enzymes whereas phosphoethanolamine, choline phosphate, and I1P are potential products of phospholipase C-class enzymes. These results suggest that LTH altered complex lipid metabolism; however, the balance among membrane phospholipid degradation, remodeling, and synthesis could not be judged from the metabolic profile alone. Of importance, hypoxia can lead to imbalance of liver lipid homeostasis and is a risk factor for non-alcoholic fatty liver diseases and steatohepatitis [57]. Thus, hypoxia induced changes in lipid metabolism in carotid arteries may further lead to atherosclerosis and stiffening.


Metabolic Profiles in Ovine Carotid Arteries with Developmental Maturation and Long-Term Hypoxia.

Goyal R, Longo LD - PLoS ONE (2015)

Box plots of the membrane lipid hydrolysis pathway comparing the six study groups.In each diagram are shown from left to right: normoxic and hypoxic fetus; normoxic and hypoxic newborn (NB); and normoxic and hypoxic adult. The Fig also demonstrates an overview of the membrane lipid hydrolysis pathway Upward red arrow means significantly (P < 0.05) higher for the noted comparison. Downward green arrow means significantly (P < 0.05) lower for the noted comparison. Upward and downward arrows together means approach significance (0.05 < P < 0.1). N = 8 in each group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482414&req=5

pone.0130739.g007: Box plots of the membrane lipid hydrolysis pathway comparing the six study groups.In each diagram are shown from left to right: normoxic and hypoxic fetus; normoxic and hypoxic newborn (NB); and normoxic and hypoxic adult. The Fig also demonstrates an overview of the membrane lipid hydrolysis pathway Upward red arrow means significantly (P < 0.05) higher for the noted comparison. Downward green arrow means significantly (P < 0.05) lower for the noted comparison. Upward and downward arrows together means approach significance (0.05 < P < 0.1). N = 8 in each group.
Mentions: Metabolites indicating the hydrolysis of phosphatidylcholines, phosphatidylglycerol [56], and phosphatidylinositol-1-phosphate—namely, glycerophosphocholine (GPC), glycerol-2-phosphate (G2P), and inositol-1-phosphate (I1P)—were elevated in at least one of the age groups acclimated to high altitude relative to their normoxic controls (Fig 7). Glycerol-3-phosphate (G3P), choline phosphate, and phosphoethanolamine, which are potential markers of phospholipid degradation but also can serve as substrates for phospholipid synthesis, also were elevated in the hypoxic newborn carotid arteries. A range of lysophospholipids containing an acyl group at the sn-1 position on the glycerol backbone—for example 1-palmitoylglycerophosphocholine and 1-stearolyglycerophosphoserine—were decreased in the LTH acclimatized newborns, and, to a lesser extent in the fetuses. Lysolipids with the sn-1 configuration are the products of phospholipase A2 (PLA2) enzymes whereas phosphoethanolamine, choline phosphate, and I1P are potential products of phospholipase C-class enzymes. These results suggest that LTH altered complex lipid metabolism; however, the balance among membrane phospholipid degradation, remodeling, and synthesis could not be judged from the metabolic profile alone. Of importance, hypoxia can lead to imbalance of liver lipid homeostasis and is a risk factor for non-alcoholic fatty liver diseases and steatohepatitis [57]. Thus, hypoxia induced changes in lipid metabolism in carotid arteries may further lead to atherosclerosis and stiffening.

Bottom Line: Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia.LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression.Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation.

View Article: PubMed Central - PubMed

Affiliation: Center for Perinatal Biology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, California, United States of America.

ABSTRACT

Background: Long-term hypoxia (LTH) is an important stressor related to health and disease during development. At different time points from fetus to adult, we are exposed to hypoxic stress because of placental insufficiency, high-altitude residence, smoking, chronic anemia, pulmonary, and heart disorders, as well as cancers. Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia. Similarly, prolonged hypoxic exposure during adult life can lead to acute mountain sickness, chronic fatigue, chronic headache, cognitive impairment, acute cerebral and/or pulmonary edema, and death.

Aim: LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression. Importantly, during the intrauterine life, a fetus is under a relative hypoxic environment, as compared to newborn or adult. Thus, the changes in gene expression with development from fetus to newborn to adult may be as a consequence of underlying changes in the metabolic profile because of the hypoxic environment along with developmental maturation. To examine this possibility, we examined the metabolic profile in carotid arteries from near-term fetus, newborn, and adult sheep in both normoxic and long-term hypoxic acclimatized groups.

Results: Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation.

No MeSH data available.


Related in: MedlinePlus