doi: 10.1161/01.RES.0000200398.52220.cc
© 2006 American Heart Association, Inc.
Editorials |
Induction of HIF-1
and iNOS With siRNA
A Novel Mechanism for Myocardial Protection
From the Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY.
Correspondence to David J. Lefer, PhD, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail dlefer@aecom.yu.edu
See related article, pages 133–140
Key Words: siRNA • prolyl 4-hydroxylase-2 • gene silencing • myocardial infarction • cardiac function
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcriptional complex composed of HIF-1
and HIF-1ß subunits that has been recognized primarily for its role in the maintenance of oxygen and energy homoeostasis.1–3 Although the HIF-1ß subunit is constitutively expressed, the expression and function of HIF-1 are precisely regulated by cellular oxygen concentrations.1–3 Under conditions of normoxia HIF-1 is rapidly degraded by the 26S proteasome and nonfunctional whereas HIF-1 accumulates instantaneously under hypoxic conditions.3–5 HIF-1 represents a highly important redox-sensitive transcription factor that regulates the expression of numerous genes under pathological conditions including: heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), VEGF, glycolytic enzymes, glucose transporters, erythropoietin, and insulin-like growth factor 2 (IGF-2).4,5 All of these genes encode proteins that are prosurvival in nature and can result in cytoprotection. Because the HIF-1 subunit is highly sensitive to oxygen and is degraded by the proteasome after prolyl-hydroxylation and ubiquitination in normoxic cells, attempts have been made to enhance the expression of HIF-1 as a means to protect cells against ischemic injury. Previous studies have demonstrated that stable expression or activation of HIF-1 can protect isolated cardiac myocytes6 and isolated hearts7 against ischemia-reperfusion (I/R) injury. Additionally, it has been previously reported that inducible nitric oxide synthase (iNOS) is regulated under conditions of hypoxia by HIF-1 in cardiac myocytes.8
In the present issue of Circulation Research Natarajan and colleagues9 have reported that inhibition of HIF-1-prolyl-4-hydroxylase-2 (PDH2) with small interfering RNA (siRNA) protects the ischemic-reperfused murine myocardium. In these carefully performed experiments these investigators treated mice
Related Article:
Circ. Res. 2006 98: 133-140.