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

By Shweta Rane, Minzhen He, Danish H Sayed, H. Vashistha, A. Malhotra, J. Sadoshima, D. Vatner, S. Vatner, M. Abdellatif. Circulation Research, 2009

622 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Electrical and Electronic Engineering, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/96e06b31e15303f674db1eee08e97e8e3f757575

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. N. Prabhakar
2. Jong-Wan Park
3. Junjie Chen
4. Ji‐Hong Lim
5. Ja-Eun Kim
6. Yoon-Mi Lee
7. Y. Chun
8. Danish H Sayed

In Pathology and Forensic Medicine

1. G. Semenza

Citations in the corpus

• ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, background): “HIF-1 and HIF-2 are essential for acute O2 sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization.”
• Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “In contrast, intermittent hypoxia and reoxygenation, not continuous hypoxia, upregulate SIRT1 regardless of redox balance, which stabilizes hypoxia-inducible factor 1a (HIF-1a) (Rane et al., 2009).”
• MicroRNAs in development and disease. (2011, background): “Sirt1 is also a direct and validated target of miR-199a-5p that complements it function by downregulating prolyl hydroxylase 2 and, thereby, stabilizing Hif-1 (497).”