294 - Hyperoxia-Induced AMPK activation protects Atrial Cardiomyocytes from ROS but inhibits their Proliferation.

Poster Board #: 294
Publication #: 3903-HP-QA.294

Background: Prematurity increases risk for diastolic heart failure later in life through poorly understood mechanisms. We recently showed exposing mice to hyperoxia from postnatal day (PND) 0 to 4 inhibited the expansion of left atrial cardiomyocyte (CM) by suppressing genes needed for fatty acid synthesis. Transcriptional profiling showed that hyperoxia also upregulates targets of AMP-dependent protein kinase (AMPK), a metabolic master regulator that promotes energy producing processes such as mitochondrial biogenesis and b-oxidation at the expense of energy consuming processes like fatty acid synthesis and proliferation.


Objective: To understand how the neonatal hyperoxia-induced AMPK activation alters fatty acid metabolism, and inhibits the proliferation and survival in atrial CMs.


Design/Methods: Affymetrix arrays were used to compare genes expressed in the atria of PND4 mice exposed to room air or 100% oxygen. Immunostaining, qRT-PCR, and western blotting were used to validate gene expression changes. Effects of hyperoxia on proliferation, survival and gene expression were also studied in the HL-1 line of mouse atrial CMs.


Results: While[MOR1] overexpressing fatty acid synthase (Fasn) partially restored the proliferation and survival of HL-1 cells in hyperoxia, it further increased their hyperoxia-dependent production of mitochondrial-derived reactive oxygen species (mtROS). Moreover, exogenous palmitate did not affect the mitochondrial activity of HL-1 cells grown in room air but increased the oxygen consumption and mtROS production of HL-1 cells [MOR2] that had previously been grown in hyperoxia[MOR3] , suggesting hyperoxia permanently alters lipid metabolism in these cells. These hyperoxia-dependent changes were associated with increased activity of AMPK both in vivo and in vitro. Moreover, the AMPK activator AICAR inhibited the expression of fatty acid synthase (Fasn) protein and slowed the growth of HL-1 cells in room air, suggesting AMPK activation may help mediate the inhibitory effects of neonatal hyperoxia on the postnatal expansion of atrial CMs.

Conclusion(s): Based on these data, we postulate that atrial CMs initially suppress fatty acid synthesis to reduce the production of mtROS in hyperoxia. However, this causes the permanent activation of AMPK, which becomes maladaptive when mice are returned to room air because it promotes b-oxidation and the subsequent production of mtROS that inhibits proliferation, and thus contribute to the development of diastolic heart failure in hyperoxia-exposed mice.

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Authors/Institutions: Ethan D. Cohen, University of Rochester SMD, Rochester, New York, United States; Min Yee, University of Rochester, Rochester, New York, United States; George A. Porter, University of Rochester Medical Center, Rochester, New York, United States; Andrew McDavid, University of Rochester, Rochester, New York, United States; Paul Brookes, University of Rochester, Rochester, New York, United States; Gloria Pryhuber, University of Rochester, Rochester, New York, United States; Michael A. O'Reilly, The University of Rochester, Rochester, New York, United States