of miR-199a derepresses hypoxia-inducible factor-1α and sirtuin 1 and recapitulates hypoxia preconditionin in cardiac myocytes. Circ Res 2009

Abstract—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. (Circ Res. 2009;104:879-886.) Key Words: miR-199a Hif-1 Sirt1 preconditioning MicroRNAs (miRNAs) are 20-nt oligoribonucleotidesthat specifically target mRNA and inhibit translation or induce its degradation. Each has the potential to regulate a set of specific genes that are involved in a common cellular function. For example, an array of growth-promoting gene