Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes.
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)-1alpha. Replenishing miR-199a during hypoxia inhibits Hif-1alpha 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-1alpha 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-1alpha. 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.
Rane
Shweta
S
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, Division of Nephrology, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
He
Minzhen
M
Sayed
Danish
D
Vashistha
Himanshu
H
Malhotra
Ashwani
A
Sadoshima
Junichi
J
Vatner
Dorothy E
DE
Vatner
Stephen F
SF
Abdellatif
Maha
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D014161:Transduction, Genetic
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D011393:Procollagen-Proline Dioxygenase; C580731:Egln1 protein, rat; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D010100:Oxygen