Published online before print March 5, 2009, doi: 10.1161/CIRCRESAHA.108.193102
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Submitted on December 19, 2008
Revised on February 22, 2008
Accepted on February 24, 2009
Downregulation of MiR-199a Derepresses Hypoxia-Inducible Factor-1
and Sirtuin 1 and Recapitulates Hypoxia Preconditioning in Cardiac Myocytes
Shweta Rane ;
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.
* To whom correspondence should be addressed. 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