Hypoxia Inducible Factor-1 Activation by Prolyl 4-Hydroxylase-2 Gene Silencing Attenuates Myocardial Ischemia Reperfusion Injury

• Published in: Circulation research 2006-01, Vol.98 (1), p.133-140
• Main Authors: Natarajan, Ramesh, Salloum, Fadi N, Fisher, Bernard J, Kukreja, Rakesh C, Fowler, Alpha A
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Cells, Cultured; Coronary heart disease; Fundamental and applied biological sciences. Psychology; Gene Silencing; Heart; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Male; Medical sciences; Mice; Mice, Inbred C3H; Myocardial Reperfusion Injury - prevention & control; Myocarditis. Cardiomyopathies; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - physiology; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - genetics; RNA, Messenger - analysis; RNA, Small Interfering - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000197816.63513.27

Hypoxia inducible factor-1 (HIF-1) regulates changes in transcription of key genes such as inducible NO synthase (iNOS) in hypoxic/ischemic environments. In normoxia, HIF-1 activation is controlled by HIF-1α-prolyl 4-hydroxylases, which target HIF-1α for ubiquitination and proteasomal degradation. We hypothesized that normoxic HIF-1 preservation could attenuate cardiac ischemia/reperfusion injury via a preconditioning effect. HIF-1 preservation was achieved by using small interfering RNA (siRNA) to silence murine HIF-1α-prolyl-4 hydroxylase-2 (PHD2). PHD2 siRNA reduced PHD2 mRNA expression 89±1.5% (P