Attenuation of the hypoxia-induced miR-34a protects cardiomyocytes through maintenance of glucose metabolism.

Ischemic injury in the heart is associated with death of cardiomyocytes and even after decades of research there is no appropriate therapeutic intervention to treat ischemic injury. The microRNA miR-34a is known to be induced in cardiomyocytes following ischemic injury. Another hallmark of ischemic injury is impaired glycolysis. The objective of the current study was to investigate the effects of short- and long-term exposure to hypoxia on miR-34a expression on apoptosis and regulation of key glycolysis metabolic enzymes. Both repeated short-term (30 min) burst of hypoxia with intermittent reoxygenation (30 min) as well as long-term (4 h) exposure to hypoxia followed by 6 h of reoxygenation robustly induced miR-34a levels. Hypoxia induced changes in cardiac permeability and localization of the channel protein connexin 34 as well as induced apoptosis as evident by levels of cleaved-caspase 3/7 and impaired cell proliferation. Hypoxia was also associated with decreased expression of key glycolytic enzymes hexokinase-1, hexokinase-2, glucose-6-phosphate-isomerase, and pyruvate dehydrogenase kinase 1. Attenuation of hypoxia-induced miR-34a by anti-miR-34a antagomir, but not a control antagomir, decreased miR-34a levels to those observed under normoxia and also inhibited apoptosis, potentially by rescuing expression of the key glycolytic enzymes. Cumulatively, our results establish that therapeutic targeting of miR-34a via antagomir might be a potent therapeutic mechanism to treat ischemic injury in the heart.