Abstract 16056: Acute HIF Prolyl Hydroxylase 2 Inactivation Confers Protection Against Myocardial Ischemic Reperfusion Injury
Background: How cardiomyocytes respond to hypoxia is a fundamental question in cardiovascular biology and relevant to many clinical phenomena including ischemic preconditioning. Hypoxia-Inducible Factor (HIF) is a master transcription factor that plays a pivotal role in the transcriptional response to hypoxia. HIF is primarily regulated post-transcriptionally and by HIF-prolyl hydroxylases (PHDs), which are oxygen-sensitive enzymes that translate changes in oxygen bioavailability to HIF stability and HIF transcriptional activity. In this regard, PHDs serve as “oxygen sensors” in mammalian cells. We hypothesized that acute inactivation of PHD2, the main HIF prolyl hydroxylase, protects the heart during ischemic-reperfusion injury.
Methods and Results: Mice with cardiac-specific PHD2 inactivation (PHD2F/F; αMHC-Cre), as well as mice where PHD2 is acutely, systemically and genetically inactivated using tamoxifen (PHD2F/F; Cre-ER) were subjected to ischemia/reperfusion (I/R) injury. We used both an in vivo model (where the proximal LAD is temporarily ligated), as well as an ex vivo langendorff model for ischemia-reperfusion injury. In both models, PHD2 inactivation led to significant cardiac protection. The cardioprotection was PHD2 specific, as inactivation of other PHD isoforms (PHD1 and PHD3) did not confer protection. In addition, pharmacological treatment of wild type mice with a PHD inhibitor prior to I/R injury also conferred protection. A number of HIF target genes were shown to be upregulated in the absence of PHD2 that play an important role in cardioprotection. These include genes involved in metabolism, autophagy, and inflammation, as well as genes regulating mitochondrial function.
Conclusions: We show that genetic and pharmacological inactivation of PHDs (and specifically PHD2) confers protection in the setting of acute cardiac I/R injury, using both in vivo and ex vivo cardiac ischemic injury models. Although studies are currently underway to delineate the mechanisms by which PHD inactivation leads to cardiac protection, preliminary evidence suggests upregulation of a number of HIF target genes involved in metabolism and mitochondrial homeostasis and integrity.
- © 2011 by American Heart Association, Inc.