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

• DOI: 10.1161/circresaha.108.193102
• Publication Date: 2009-03-06T05:09:14Z
• Authors: Shweta Rane; Minzhen He; Danish Sayed; Himanshu Vashistha; Ashwani Malhotra; Junichi Sadoshima; Dorothy E. Vatner; Stephen F. Vatner; Maha Abdellatif
• Keywords: 0301 basic medicine; Myocardial Ischemia; Procollagen-Proline Dioxygenase; Down-Regulation; Apoptosis; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; Mitochondria, Heart; Hypoxia-Inducible Factor-Proline Dioxygenases; 3. Good health; Mice, Inbred C57BL; Oxygen; Disease Models, Animal; Mice; MicroRNAs; 03 medical and health sciences; Animals, Newborn; Gene Knockdown Techniques; Ischemic Preconditioning, Myocardial; Animals; Humans; Myocytes, Cardiac; Cells, Cultured

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)-1α. Replenishing miR-199a during hypoxia inhibits Hif-1α 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-1α 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-1α. 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.