Hypoxia-Inducible Factor 1 in Lower Limb Ischemia

Vascular ◽  
2006 ◽  
Vol 14 (6) ◽  
pp. 321-327 ◽  
Author(s):  
Teik K. Ho ◽  
David J. Abraham ◽  
Carol M. Black ◽  
Daryll M. Baker
Keyword(s):  
Skeletal Muscle ◽  
Lower Limb ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Hypoxia Inducible Factor ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
Western World ◽  
High Morbidity ◽  
Activity Increase

In the Western world, peripheral vascular disease (PVD) has a high prevalence and is associated with high morbidity and mortality. More patients are presenting with critical limb ischemia (CLI), the end stage of PVD, because of an increased life expectancy owing to improved medical care. In a large percentage of these patients, lower limb amputation is still required, despite current advances in surgery and interventional radiology. Studies of ischemic skeletal muscles disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Many of the genes responsible for these responses are regulated by hypoxia-inducible factor (HIF)-1. HIF-1, consisting of HIF-1α and HIF-1β subunits, is a major transcription factor that functions as a master regulator of oxygen homeostasis that plays essential roles in cellular and systemic pathophysiology. HIF-1α expression and HIF-1 transcriptional activity increase exponentially as cellular oxygen concentration is decreased. More than 60 target genes that are transactivated by HIF-1 have been identified. Many of the target genes, such as vascular endothelial growth factor, have been studied extensively, especially in tumors. However, only recently that interest in HIF-1 is growing in relation to ischemic diseases. Most of the studies concentrated mainly on the angiogenic property of HIF-1. In contrast, there is a lack of information on the role of HIF-1 in skeletal muscle metabolic adaptive changes as the end-organ in PVD. This review aims to summarize our current understanding of HIF-1 roles and the therapeutic potential in PVD.

scholarly journals Stromal-Cell-Derived Factor-1 (SDF-1)/CXCL12 as Potential Target of Therapeutic Angiogenesis in Critical Leg Ischaemia

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Teik K. Ho ◽  
X. Shiwen ◽  
D. Abraham ◽  
J. Tsui ◽  
D. Baker
Keyword(s):  
Skeletal Muscle ◽  
Chemokine Receptors ◽  
Stromal Cell ◽  
Therapeutic Angiogenesis ◽  
Limb Amputation ◽  
Western World ◽  
High Morbidity ◽  
Biologic Effects ◽  
Inflammatory Processes ◽  
Stromal Cell Derived Factor

In the Western world, peripheral vascular disease (PVD) has a high prevalence with high morbidity and mortality. In a large percentage of these patients, lower limb amputation is still required. Studies of ischaemic skeletal muscle disclosed evidence of endogenous angiogenesis and adaptive skeletal muscle metabolic changes in response to hypoxia. Chemokines are potent chemoattractant cytokines that regulate leukocyte trafficking in homeostatic and inflammatory processes. More than 50 different chemokines and 20 different chemokine receptors have been cloned. The chemokine stromal-cell-derived factor-1 (SDF-1 aka CXCL12) is a constitutively expressed and inducible chemokine that regulates multiple physiological processes, including embryonic development and organ homeostasis. The biologic effects of SDF-1 are mediated by chemokine receptor CXCR4, a 352 amino acid rhodopsin-like transmembrane-specific G protein-coupled receptor (GPCR). There is evidence that the administration of SDF-1 increases blood flow and perfusion via recruitment of endothelial progenitor cells (EPCs). This review will focus on the role of the SDF-1/CXCR4 system in the pathophysiology of PVD and discuss their potential as therapeutic targets for PVD.

scholarly journals Targeting hypoxia-inducible factor 1 to stimulate tissue vascularization

2016 ◽  
Vol 64 (2) ◽  
pp. 361-363 ◽  
Author(s):  
Gregg L Semenza
Keyword(s):  
Growth Factor ◽  
Transplant Rejection ◽  
Hypoxia Inducible Factor ◽  
Limb Ischemia ◽  
Tissue Perfusion ◽  
Therapeutic Benefit ◽  
Limb Amputation ◽  
Loss Of Function ◽  
Chemical Inducers ◽  
Hypoxia Inducible Factor 1

When tissue perfusion is impaired, the resulting reduction in O2 availability activates hypoxia-inducible factor 1 (HIF-1), which mediates increased transcription of genes encoding multiple angiogenic factors including vascular endothelial growth factor, stromal-derived factor 1, placental growth factor, and angiopoietins, leading to the mobilization of bone marrow-derived angiogenic cells, increased angiogenesis, and arterial remodeling. These HIF- 1-dependent responses are impaired by aging or loss of function mutations at the locus encoding the HIF-1α subunit. in mouse models of limb ischemia and lung transplant rejection, the augmentation of HIF-1 activity by gene therapy or chemical inducers was associated with maintenance of tissue perfusion that prevented limb amputation and allograft rejection, respectively. Thus, targeting HIF-1 may be of therapeutic benefit in these clinical contexts and others in which impaired tissue perfusion plays a role in disease pathogenesis.

scholarly journals POOR PROGNOSTIC DETERMINANTS FOR PATIENTS UNDERGOING SUPERFICIAL FEMORAL ARTERY ANGIOPLASTY

2020 ◽  
Vol 8 (11) ◽  
pp. 828-831
Author(s):  
S. Maruthu Thurai ◽  
◽  
P. Mohan Raja ◽  
M. Murali ◽  
◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Femoral Artery ◽  
Critical Limb Ischemia ◽  
Superficial Femoral Artery ◽  
Lower Limb ◽  
Prospective Observational Study ◽  
Negative Impact ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
The Poor

Introduction: Aim is to study the poor prognostic determinants for patients undergoing superficial femoral artery angioplasty . Material and Methods: It is a Prospective observational study done in fifty patients who has undergone superficial femoral artery angioplasty for lower limb ischemia. Results: 22% had reocclusion of lesion, 10% required reintervention and 8% underwent major limb amputation .These three were considered major negative impact conditions. These were found in majority of patients with renal insufficiency, critical limb ischemia, smoker and drug defaulters. Conclusion: Thus poor prognostic determinants in the study were renal insufficiency, critical limb ischemia , smoker and drug defaulters.

Lower limb amputation following venous cannulation for VA-ECMO: a case report

Perfusion ◽  
2021 ◽  
pp. 026765912110506
Author(s):  
Natasha Habr ◽  
Jamal J Hoballah ◽  
Jamil Borgi ◽  
Caroline Hamadi ◽  
Pierre Sfeir ◽  
...  
Keyword(s):  
Lower Limb ◽  
Limb Ischemia ◽  
Major Amputation ◽  
Lower Limb Amputation ◽  
Limb Amputation ◽  
Venous Cannulation ◽  
Knee Amputation ◽  
Venous Cannula ◽  
Arterial Insufficiency ◽  
Va Ecmo

Lower limb amputation following arterial cannulation for VA-ECMO has been described in the literature. Limb ischemia however following venous cannulation is very rare and not quite understood. We present a case of limb ischemia following venous cannulation. A combination of venous congestion, compartment syndrome and subsequent arterial insufficiency is the proposed pathophysiology. Shock and use of vasopressors are compounding factors. Limb ischemia can be transient and reversible if diagnosed immediately and treated by early removal of the cannula. Our patient was unstable and ECMO dependent, and removal of the cannula was not an option. This resulted in limb loss and eventual above knee amputation. Use of the smallest appropriate venous cannula and early fasciotomy, in addition to hemodynamic optimization are measures that could help in preventing major amputation.

scholarly journals Metabolic reprogramming by HIF-1 promotes the survival of bone marrow–derived angiogenic cells in ischemic tissue

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4988-4998 ◽  
Author(s):  
Sergio Rey ◽  
Weibo Luo ◽  
Larissa A. Shimoda ◽  
Gregg L. Semenza
Keyword(s):  
Bone Marrow ◽  
Target Genes ◽  
Ex Vivo ◽  
Marrow Cell ◽  
Hypoxia Inducible Factor ◽  
Lactate Production ◽  
Limb Ischemia ◽  
Metabolic Reprogramming ◽  
Low Oxygen ◽  
Ischemic Tissue

Abstract A major obstacle to using bone marrow cell-based therapies for ischemic cardiovascular disease is that transplanted cells must survive in an ischemic microenvironment characterized by low oxygen, glucose, and pH. We demonstrate that treatment of bone marrow-derived angiogenic cells (BMDACs) with dimethyloxalylglycine, an α-ketoglutarate antagonist that induces hypoxia-inducible factor 1 (HIF-1) activity, results in metabolic reprogramming of these cells, with increased glucose uptake, decreased O2 consumption, increased lactate production, decreased reactive oxygen species, and increased intracellular pH. These effects are dependent on HIF-1, which transactivates target genes encoding metabolic enzymes and membrane transporters. Dimethyloxalylglycine-treated BMDACs have a significant survival advantage under conditions of low O2 and low pH ex vivo and in ischemic tissue. Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.

scholarly journals Expression of HIF-1α and VEGF in Skeletal Muscle of Plateau Animals in Response to Hypoxic Stress

2014 ◽  
pp. 801-805
Author(s):  
H.-C. XIE ◽  
J.-P. HE ◽  
J.-F. ZHU ◽  
J.-G. LI
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Stress ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Sd Rats ◽  
Hypoxic Environment ◽  
Endothelial Growth Factor

Hypoxia-inducible factor-1α (HIF-1α) transcriptionally regulates expression of several target genes in protecting tissues against hypoxia. With hypoxic stress, vascular endothelial growth factor (VEGF) is a signal protein produced by cells and further contributes to improvement of vascular functions and restoring the oxygen supply to tissues. In this current study, we first hypothesized that the protein levels of HIF-1α and VEGF are reduced in skeletal muscles of plateau animals [China Qinghai-Tibetan plateau pikas (ochotona curzoniae)] in response to hypoxia as compared with control animals [normal lowland Sprague-Dawley (SD) rats]. We further hypothesized that HIF-1α plays a role in regulating expression of VEGF in skeletal muscle. Note that HIF-1α and VEGF were determined by using two-site immunoenzymatic assay (ELISA) methods. Our results demonstrated that hypoxic stress induced by exposure of lower O2 (6 h) significantly increased the levels of HIF-1α and VEGF in the oxidative and glycolytic muscles of SD rats and pikas (P<0.05 vs. normoxic conditions). Notably, the increases in HIF-1α and VEGF were significantly less in pikas (P<0.05, vs. SD controls) than in SD rats. In addition, a linear relationship was observed between amplified HIF-1α and VEGF in oxidative muscle (r=0.76 and P<0.01) and glycolytic muscle (r=0.72 and P<0.01) and inhibiting HIF-1α significantly decreased expression of VEGF induced by hypoxic stress in skeletal muscles (P<0.05). Overall, our findings suggest that (1) responsiveness of HIF-1α and VEGF in skeletal muscles to hypoxic stress is blunted in plateau animals, and (2) HIF-1α has a regulatory effect on VEGF under hypoxic environment.

scholarly journals Transplantation of Adipose Stromal Cell Sheet Producing Hepatocyte Growth Factor Induces Pleiotropic Effect in Ischemic Skeletal Muscle

2019 ◽  
Vol 20 (12) ◽  
pp. 3088 ◽  
Author(s):  
Maria A. Boldyreva ◽  
Evgeny K. Shevchenko ◽  
Yuliya D. Molokotina ◽  
Pavel I. Makarevich ◽  
Irina B. Beloglazova ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Therapeutic Potential ◽  
Cell Sheet ◽  
Limb Ischemia ◽  
Pleiotropic Effect ◽  
Neuroprotective Effects ◽  
Adipose Derived Stromal Cells ◽  
Hepatocyte Growth

Cell therapy remains a promising approach for the treatment of cardiovascular diseases. In this regard, the contemporary trend is the development of methods to overcome low cell viability and enhance their regenerative potential. In the present study, we evaluated the therapeutic potential of gene-modified adipose-derived stromal cells (ADSC) that overexpress hepatocyte growth factor (HGF) in a mice hind limb ischemia model. Angiogenic and neuroprotective effects were assessed following ADSC transplantation in suspension or in the form of cell sheet. We found superior blood flow restoration, tissue vascularization and innervation, and fibrosis reduction after transplantation of HGF-producing ADSC sheet compared to other groups. We suggest that the observed effects are determined by pleiotropic effects of HGF, along with the multifactorial paracrine action of ADSC which remain viable and functionally active within the engineered cell construct. Thus, we demonstrated the high therapeutic potential of the utilized approach for skeletal muscle recovery after ischemic damage associated with complex tissue degenerative effects.

scholarly journals Type 2 diabetes impairs the ability of skeletal muscle pericytes to augment postischemic neovascularization in db/db mice

2018 ◽  
Vol 314 (5) ◽  
pp. C534-C544 ◽  
Author(s):  
Katherine L. Hayes ◽  
Louis M. Messina ◽  
Lawrence M. Schwartz ◽  
Jinglian Yan ◽  
Amy S. Burnside ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Therapeutic Potential ◽  
Limb Ischemia ◽  
Wild Type ◽  
Collateral Arteries ◽  
Collateral Artery

Peripheral artery disease is an atherosclerotic occlusive disease that causes limb ischemia and has few effective noninterventional treatments. Stem cell therapy is promising, but concomitant diabetes may limit its effectiveness. We evaluated the therapeutic potential of skeletal muscle pericytes to augment postischemic neovascularization in wild-type and type 2 diabetic (T2DM) mice. Wild-type C57BL/6J and leptin receptor spontaneous mutation db/db T2DM mice underwent unilateral femoral artery excision to induce limb ischemia. Twenty-four hours after ischemia induction, CD45−CD34−CD146+ skeletal muscle pericytes or vehicle controls were transplanted into ischemic hindlimb muscles. At postoperative day 28, pericyte transplantation augmented blood flow recovery in wild-type mice (79.3 ± 5% vs. 61.9 ± 5%; P = 0.04), but not in T2DM mice (48.6% vs. 46.3 ± 5%; P = 0.51). Pericyte transplantation augmented collateral artery enlargement in wild-type (26.7 ± 2 μm vs. 22.3 ± 1 μm, P = 0.03), but not T2DM mice (20.4 ± 1.4 μm vs. 18.5 ± 1.2 μm, P = 0.14). Pericyte incorporation into collateral arteries was higher in wild-type than in T2DM mice ( P = 0.002). Unexpectedly, pericytes differentiated into Schwann cells in vivo. In vitro, Insulin increased Nox2 expression and decreased tubular formation capacity in human pericytes. These insulin-induced effects were reversed by N-acetylcysteine antioxidant treatment. In conclusion, T2DM impairs the ability of pericytes to augment neovascularization via decreased collateral artery enlargement and impaired engraftment into collateral arteries, potentially via hyperinsulinemia-induced oxidant stress. While pericytes show promise as a unique form of stem cell therapy to increase postischemic neovascularization, characterizing the molecular mechanisms by which T2DM impairs their function is essential to achieve their therapeutic potential.

The Effect of Malignancy on Outcomes Following Revascularization for Critical Limb Ischemia: A Case–Control Study

2018 ◽  
Vol 52 (5) ◽  
pp. 325-329
Author(s):  
Tom Calderbank ◽  
Ahmed Karim ◽  
Mike Wall ◽  
Arooj Syed ◽  
Robert S. M. Davies ◽  
...  
Keyword(s):  
Lower Limb ◽  
Case Control Study ◽  
Limb Ischemia ◽  
Case Control ◽  
Limb Amputation ◽  
Prospective Data ◽  
Using Data ◽  
Nested Case Control ◽  
Control Study ◽  
Prospective Analyses

Aim: Malignancy is common in patients presenting with critical lower limb ischemia (CLI). However, outcomes in patients with concomitant active malignancy and CLI have not been well defined in comparative prospective analyses. Using contemporary prospective data, we aimed to assess outcomes following revascularization in patients with CLI and active malignancy. Methods: A nested case–control study was performed using data from 2 tertiary referral centers for vascular disease. A total of 48 consecutive patients undergoing intervention for CLI who had a diagnosis of active malignancy were identified and matched to patients with CLI but no malignancy for age, sex, diabetes, and smoking. Patency rates and morbidity/mortality were assessed using duplex ultrasonography and regular clinical review. Results: A total of 48 consecutive patients (median age: 74.5 years; interquartile range: 68-80 years) with active malignancy and CLI were identified and case-matched (age, sex, diabetes, and smoking) to 48 patients undergoing intervention for CLI who had no malignancy. Major cardiovascular risk factors did not differ. All-cause mortality was 23% versus 12% ( P = .41) at 6 months and 54% versus 15% ( P < .001) at 12 months. None of the patients died due to complications relating directly to the lower limb intervention or within 30 days of the intervention. A total of 4 (8.3%) patients had required a major limb amputation at 6 months in both groups, compared with 5 (10.4%) patients with malignancy versus 4 (8.3%) patients without ( P = .73) at 12 months. Patency rates were similar at 12 months (73% vs 80%). Three patients had required reintervention in both groups (endovascular in all cases) at 12 months. Conclusion: Revascularization can be offered safely in selected patients with active malignancy; patency rates in those surviving to 1 year are similar to patients without malignancy.

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