• Shweta Rane, Minzhen He, Danish Sayed, Himanshu Vashistha, Ashwani Malhotra, Junichi Sadoshima, Dorothy E Vatner, Stephen F Vatner, and Maha Abdellatif.
• 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.
• Circ. Res. 2009 Apr 10; 104 (7): 879-86.

AbstractMicroRNAs 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.

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