Cell Type–Specific Regulation of Angiogenic Growth Factor Gene Expression and Induction of Angiogenesis in Nonischemic Tissue by a Constitutively Active Form of Hypoxia-Inducible Factor 1

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Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.cardiac surgery | cardioprotection | coronary heart disease | myocardial infarction C oronary heart disease (CHD) is the leading cause of mortality in the US population, accounting for one in every six deaths, at a rate of one death from CHD every minute (1). Coronary artery stenosis due to atherosclerotic plaques results in reduced perfusion and myocardial ischemia. Plaque rupture results in complete arterial occlusion and the death of cardiac cells (myocardial infarction; MI) due to oxygen deprivation (2). Rapid reperfusion by thrombolytic therapy or percutaneous coronary intervention is the most important clinical factor to limit infarct size (IS), while at the same time reperfusion contributes to tissue injury by increasing intracellular reactive oxygen species and Ca 2+ levels (3, 4). Exposure of the heart to short (5-min) episodes of ischemia (I 5 ) and reperfusion (R 5 ) protects the heart against injury caused by a subsequent prolonged episode of ischemia and reperfusion (IR), a phenomenon known as ischemic preconditioning (IPC) (5).Although IPC was shown to have a powerful protective effect in animal models, the obvious difficulties involved in subjecting the heart to direct IPC restrict its potential clinical applications. However, the discovery that an IPC stimulus applied to the circumflex coronary artery reduced the size of an MI arising from sustained occlusion of the left anterior descending artery (6) was subsequently extended by the demonstration that the heart could be protected by su...

Section: Resultsmentioning

confidence: 99%

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Cai

Luo

Zhan

et al. 2013

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142

“…To determine the effect of HIF-1 gain of function, we exposed DRG cultures bearing established axons to recombinant adenoviral vector encoding either β-galactosidase (AdLacZ) or a constitutively active form of HIF-1α (AdCA5) containing amino acid deletions and substitutions that inhibit degradation of the protein (25). We performed preliminary dosing studies using AdCA5 (which also expresses GFP) to determine the number of plaque-forming units per cell required to achieve >90% infection of Schwann cells with <1% infection of neurons in DRG cultures.…”

Section: No Donor Administration Prevents Axonal Degeneration Ex Vivomentioning

confidence: 99%

Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin

Keswani

Bosch–Marcé

Reed

et al. 2011

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Nitric oxide (NO) is a signaling molecule that can trigger adaptive (physiological) or maladaptive (pathological) responses to stress stimuli in a context-dependent manner. We have previously reported that NO may signal axonal injury to neighboring glial cells. In this study, we show that mice deficient in neuronal nitric oxide synthase (nNOS −/− ) are more vulnerable than WT mice to toxin-induced peripheral neuropathy. The administration of NO donors to primary dorsal root ganglion cultures prevents axonal degeneration induced by acrylamide in a dose-dependent manner. We demonstrate that NO-induced axonal protection is dependent on hypoxia-inducible factor (HIF)-1-mediated transcription of erythropoietin (EPO) within glial (Schwann) cells present in the cultures. Transduction of Schwann cells with adenovirus AdCA5 encoding a constitutively active form of HIF-1α results in amelioration of acrylamide-induced axonal degeneration in an EPOdependent manner. Mice that are partially deficient in HIF-1α (HIF-1α +/− ) are also more susceptible than WT littermates to toxic neuropathy. Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration.

“…HIF-2␣ is also O 2 -regulated, dimerizes with HIF-1␤, and has been implicated in vascular responses to ischemia (10,11). HIF-1 regulates the expression of genes encoding angiogenic cytokines, such as VEGF, placental growth factor (PLGF), stromal-derived factor (SDF)-1, and their cognate receptors VEGFR1, VEGFR2, and CXCR4 (12)(13)(14). HIF-1 activity decreases with age and is linked to a poor angiogenic response in old animals, which reflects deficient production of angiogenic cytokines and impaired mobilization of BMDACs (4,15,16).…”

mentioning

confidence: 99%

“…HIF-1 activity decreases with age and is linked to a poor angiogenic response in old animals, which reflects deficient production of angiogenic cytokines and impaired mobilization of BMDACs (4,15,16). AdCA5, an adenovirus encoding a constitutively active form of HIF-1␣, enhances angiogenesis, arteriogenesis, and the number of circulating angiogenic cells in animal models (4,12,17). Adeno-associated virus transduction of a stabilized form of HIF-1␣ was superior to VEGF in stimulating angiogenesis in skeletal muscle (18).…”

mentioning

confidence: 99%

Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia

Rey¹,

Lee²,

Wang

et al. 2009

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110

103