Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

Natarajan, Ramesh; Salloum, Fadi N.; Fisher, Bernard; Ownby, Evan D.; Kukreja, Rakesh C.; Fowler, Alpha A.

doi:10.1152/ajpheart.00291.2007

Cited by 68 publications

(47 citation statements)

References 51 publications

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“…HIF-1a expression is increased in hypoxaemic and inflamed tissues, and in many tumour tissues HIF-1a is known to promote tumour angiogenesis [32]. In contrast, no diseases have so far been described that are characterised by a decrease of tissue levels of the HIF-1a protein, with the exception of acute ischaemia and reperfusion of the myocardium [33,34] and the respiratory distress syndrome in pre-term lambs [35]. Decreased or impaired activity of this transcription factor has profound consequences for the homeostatic control at the cellular and mitochondrial level and will probably affect apoptosis and cellular senescence which characterise pulmonary emphysema [20,22].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia inducible factor-1α in human emphysema lung tissue

Matsumura¹,

Mizuno²,

Kraskauskas³

et al. 2010

Eur Respir J

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The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1a in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples were taken from patients with moderate COPD (n56; stage I and II Global Initiative for Chronic Obstructive Lung Disease classification) and severe COPD (n513; stage III and IV).We analysed mRNA and protein expression in the lung tissue samples and found that: 1) HIF-1a and histone deacetylase 2 proteins were significantly decreased and were correlated; 2) HIF-1a and vascular endothelial growth factor (VEGF) proteins, and forced expiratory volume in 1 s % predicted were correlated in all patients; 3) the changes in VEGF and HIF-1a protein levels in all patients were not age-related and not related to the pack-yr smoking history; and 4) the reduced HIF-1a protein expression was seen in lung endothelial cells and alveolar septal cells by immunohistochemistry.In conclusion, reduced expression of HIF-1a protein in severe COPD is consistent with the concept of a lung structure maintenance programme which is impaired on a molecular level.

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Section: Discussionmentioning

confidence: 99%

Hypoxia inducible factor-1α in human emphysema lung tissue

Matsumura¹,

Mizuno²,

Kraskauskas³

et al. 2010

Eur Respir J

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“…37 More recently, specific PHD2 silencing has been shown to enhance ventricular function and reduce infarct size in a mouse model of myocardial ischemia/reperfusion injury. 18,19 In the present study, we have developed a therapeutic strategy that promotes the local and transient inhibition of PHD1, PHD2, or PHD3. We demonstrated that PHD gene silencing promoted therapeutic revascularization in mice with hindlimb ischemia, with PHD3 attenuation leading to a better effect than similar reduction of PHD2 or PHD1.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, intraperitoneal injection of small interfering PHD (siPHD) upregulates cardiac inducible nitric oxide synthase expression, increases ventricular function, and reduces infarct size in a mouse model of myocardial ischemia/reperfusion injury. 18,19 In the present study, we used short hairpin RNAs (shRNAs) to downregulate murine PHD1, PHD2, or PHD3 levels and analyzed their efficiency as a therapeutic strategy in a model of mice hindlimb ischemia.…”

Section: Clinical Perspective On P 59mentioning

confidence: 99%

Inhibition of Prolyl Hydroxylase Domain Proteins Promotes Therapeutic Revascularization

et al. 2009

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Background-The hypoxia-inducible transcription factor (HIF) subunits are destabilized via the O 2 -dependent prolyl hydroxylase domain proteins (PHD1, PHD2, and PHD3). We investigated whether inhibition of PHDs via upregulating HIF might promote postischemic neovascularization. Methods and Results-Mice with right femoral artery ligation were treated, by in vivo electrotransfer, with plasmids encoding for an irrelevant short hairpin RNA (shRNA) (shCON [control]) or specific shRNAs directed against HIF-1␣ (shHIF-1␣), PHD1 (shPHD1), PHD2 (shPHD2), and PHD3 (shPHD3). The silencing of PHDs induced a specific and transient downregulation of their respective mRNA and protein levels at day 2 after ischemia and, as expected, upregulated HIF-1␣. As a consequence, 2 key hypoxia-inducible proangiogenic actors, vascular endothelial growth factor-A and endothelial nitric oxide synthase, were upregulated at the mRNA and protein levels. In addition, monocyte chemotactic protein-1 mRNA levels and infiltration of Mac-3-positive macrophages were enhanced in ischemic leg of mice treated with shPHD2 and shPHD3. Furthermore, activation of HIF-1␣-related pathways was associated with changes in postischemic neovascularization. At day 14, silencing of PHD2 and PHD3 increased vessel density by 2.2-and 2.6-fold, capillary density by 1.8-and 2.1-fold, and foot perfusion by 1.2-and 1.4-fold, respectively, compared with shCON (PϽ0.001). shPHD1 displayed a lower proangiogenic effect. Of interest, coadministration of shHIF-1␣ with shPHD3 abrogated shPHD3-related effects, suggesting that activation of endogenous HIF-1-dependent pathways mediated the proangiogenic effects of PHD silencing. Conclusions-We demonstrated that a direct inhibition of PHDs, and more particularly PHD3, promoted therapeutic revascularization. Furthermore, we showed that activation of the HIF-1 signaling pathway is required to promote this revascularization. (Circulation. 2009;120:50-59.)

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“…Targeting and scrambled siRNA were purchased from Santa Cruz. We used a previously validated approach of high-dose (0.45 mg/kg) systemic (intraperitoneal) injection mixed with an equal volume of siPORT amine (Ambion) in the live animal (35,36). For both cryopyrin and P2X7 a dose of 0.45 mg/kg induced a significant >80% reduction in target protein at 24 h. We then used this approach in the AMI model by administering the siRNA 24 h before surgery and then again every 72 h. Silencing efficacy was evaluated by WB using an anti-cryopyrin polyclonal antibody (Santa Cruz) and an anti-P2X7 polyclonal antibody (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

Mezzaroma

Toldo²,

Farkas³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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535

477

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Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome-apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.interleukin-1 | NALP3 | NLRP3 | pyroptosis

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Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium

Abstract: Natarajan R, Salloum FN, Fisher BJ, Ownby ED, Kukreja RC, Fowler AA 3rd. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium.

Cited by 68 publications

References 51 publications

Hypoxia inducible factor-1α in human emphysema lung tissue

Hypoxia inducible factor-1α in human emphysema lung tissue

Inhibition of Prolyl Hydroxylase Domain Proteins Promotes Therapeutic Revascularization

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

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