Voelcker Academy

Research Symposium 2011


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Diana Olshevskaya

Placenta-Specific Loss of Autophagy Causes Metabolic Abnormalities in Placenta

Diana Olshevskaya

Mentor(s): Alina Maloyan, Ph.D.

BACKGROUND: Maternal obesity predisposes the offspring to cardiovascular and metabolic diseases causing so called developmental or fetal programming. Autophagy is a process that sequesters damaged organelles and misfolded proteins in autophagosomes for degradation and recycling in lysosomes. Autophagy is initiated in response to nutrient stress. We found increased formation of autophagosomes but impaired lysosomal clearance in the placentas from overweight and obese women indicating defective autophagy. Therefore, defective placental autophagy may play a role in developmental programming with obesity.

OBJECTIVES: To determine the effect of placenta-specific deletion of the essential autophagy-related gene 7 (ATG7) on placental function.

METHODS: Cyp19-Cre-recombinase mice, which allow targeted gene expression in placenta trophoblast, were crossed to ATG7 flox/flox (wild type (WT)) mice generating the placenta-specific ATG7 null allele (KO mice). KO mice were bred onto C57BL/6 background. Placental function has been determined by Western Blots for mitochondrial antioxidant superoxide dismutase (SOD2), and peroxisome proliferator-activated receptor gamma (PPAR gamma), a nuclear receptor that has been reported to be dysregulated in numerous diseases including obesity, diabetes, atherosclerosis, and cancer.

RESULTS: The ATG7 gene was only deleted in placenta, not in any other fetal tissue. Offspring of ATG7 KO mice appeared fertile and phenotypically normal. The expression of placental SOD2 was 60% decreased in ATG7 knockout mice compared to wild type mice. Decreased expression of SOD2 has been previously shown to cause an excessive production of reactive oxygen species (ROS) and oxidative stress. In contrast, the expression of PPAR gamma was increased 2-fold in placentas of ATG7 knockout mice compared to wild type mice, suggesting metabolic abnormalities. CONCLUSIONS. We demonstrate that specific disruption of placental autophagy results in placental metabolic abnormalities and oxidative stress. (This study was supported by CTSA UL1RR025767).

Collaborators: Diana Olshevskaya, Sribalasubashini Muralimanoharan, Leslie Myatt, and Alina Maloyan