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(Circulation Research. 2009;104:879.)
© 2009 American Heart Association, Inc.

Cellular Biology

Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1 and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes

Shweta Rane, Minzhen He, Danish Sayed, Himanshu Vashistha, Ashwani Malhotra, Junichi Sadoshima, Dorothy E. Vatner, Stephen F. Vatner, Maha Abdellatif

From the Cardiovascular Research Institute (S.R., M.H., D.S., J.S., D.E.V., S.F.V., M.A.), Department of Cell Biology and Molecular Medicine; and Department of Medicine (H.V., A.M.), Division of Nephrology, University of Medicine and Dentistry of New Jersey, Newark.

Correspondence to Maha Abdellatif, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103. E-mail abdellma{at}umdnj.edu

MicroRNAs are posttranscriptional gene regulators that are differentially expressed during various diseases and have been implicated in the underlying pathogenesis. We report here that miR-199a is acutely downregulated in cardiac myocytes on a decline in oxygen tension. This reduction is required for the rapid upregulation of its target, hypoxia-inducible factor (Hif)-1. Replenishing miR-199a during hypoxia inhibits Hif-1 expression and its stabilization of p53 and, thus, reduces apoptosis. On the other hand, knockdown of miR-199a during normoxia results in the upregulation of Hif-1 and Sirtuin (Sirt)1 and reproduces hypoxia preconditioning. Sirt1 is also a direct target of miR-199a and is responsible for downregulating prolyl hydroxylase 2, required for stabilization of Hif-1. Thus, we conclude that miR-199a is a master regulator of a hypoxia-triggered pathway and can be exploited for preconditioning cells against hypoxic damage. In addition, the data demonstrate a functional link between 2 key molecules that regulate hypoxia preconditioning and longevity.

Key Words: miR-199a • Hif-1 Sirt1 • preconditioning