angiogenin and Ischemia

Cells under stressful microenvironmental conditions initiate integrated molecular circuitries that aim at reducing general protein translation rates while redirecting protein synthesis toward a selective set of stress-response proteins. The consequence of the activation of this dynamic system is a reduction of the energy expenditure of the cell, and a metabolic rewiring that shapes adaptation under stress, which will, in fine, promote cell survival. In general, the translation initiation step is the prime target of translation reduction, with 2 molcular modules inhibiting translation initiation: the mechanistic target of Rapamycin complex 1, and the stress related kinases eIF2 kinases, which are all involved in the cellular responses to kidney injuries. tRNA (tRNA) dynamics and fragmentation have recently gained a considerable weight in the field of the non-coding RNA biology, and emerge as an important system for protein translation modulation under cellular stress. More precisely, stress-induced tRNA (tiRNA), the cleavage products of the ribonuclease angiogenin, are generated under various stress conditions, including oxidative stress and endoplasmic reticulum stress, and contribute to protein translation reprogramming in mammal cells. Current clinical and experimental evidence indicates that the angiogenin-tRNA fragmentation system is initiated under renal insults, and is involved in the tissue adaptation upon kidney injury. In addition, this system represents a potential source for minimally-invasive or non invasive biomarkers of early kidney injury. Besides RNA interference, tRNA fragments are likely involved in other fundamental cellular functions, including inflammation, and a better understanding of the molecular basis of tRNA functions will drive discoveries on the fundamental role of non coding RNA biology, as exemplified by microRNA, in the regulation of kidney homeostasis.

Topics: Animals; Endoplasmic Reticulum Stress; Humans; Ischemia; Kidney; Kidney Diseases; Oxidative Stress; Protein Biosynthesis; Ribonuclease, Pancreatic; RNA, Transfer; Stress, Physiological

The efficacy and safety of gene-engineering recombinant constructions with endothelial growth factor gene and angiogenin for the treatment of the chronic lower limb ischemia were studied. 134 patients were included in prospective controlled study. The main group, who received both traditional treatment and genetic therapy, consisted of 74 patients. The rest 60 patients were included into the control group. Of 74 patients from the main group, genetic therapy was used together with conservative means in 39 patients and with reconstructive vascular operations in 35 patients. The gene-engineering angiogenesis stimulation therapy proved to be effective and safe. The combination of angiogenesis genetic stimulation with reconstructive vascular surgery demonstrated significantly better results, then monotherapy.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Chronic Disease; Female; Follow-Up Studies; Genetic Therapy; Humans; Ischemia; Leg; Male; Middle Aged; Neovascularization, Pathologic; Prospective Studies; Ribonuclease, Pancreatic; Treatment Outcome; Vascular Surgical Procedures

The authors have studied therapeutic outcomes in a total of 38 patients diagnosed with occlusions of the femoropopliteal segment. In the Study Group patients (n = 19), the operation of femoropopliteal bypass grafting was supplemented by using gene stimulators of angiogenesis (gene constructions with the genes of vascular endothelial growth factor, and angiogenin). The Control Group patients (n = 19) were subjected to a reconstructive vascular operation alone. The remote results were followed up from six to twenty-six months, having shown reliably better therapeutic outcomes obtained in the Study Group patients, as judged by the distance of pain-free walking, the time of restoration of the baseline parameters of blood flow during the treadmill test, muscular perfusion, and the quality of life indices. A conclusion was made that the use ofangiogenesis-stimulating methods combined with reconstructive vascular operations improves the long-term outcomes in patients presenting with lower limb chronic ischaemia.

Topics: Aged; Angiogenesis Inducing Agents; Blood Vessel Prosthesis; Chronic Disease; Drug Therapy, Combination; Exercise Test; Female; Follow-Up Studies; Guideline Adherence; Humans; Injections, Intramuscular; Ischemia; Leg; Male; Middle Aged; Neovascularization, Physiologic; Quality of Life; Ribonuclease, Pancreatic; Time Factors; Tissue Engineering; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Surgical Procedures

The disruption of appropriate cellular stress responses is implicated in the pathogenesis of different neurological disorders including ischemic injury. Early diagnosis and treatment are often associated with better prognosis in ischemic stroke patients. Thus, there is an urgent need to improve the speed and accuracy of stroke diagnosis by developing highly sensitive stroke biomarkers. We recently reported that transfer RNA (tRNA) was involved in cell stress response pathways. Under cell stress conditions, mature tRNA is cleaved by a specific ribonuclease, angiogenin, generating tRNA-derived stress-induced RNA (tiRNA). To study tiRNA generation in an in vitro model of ischemic-reperfusion injury, we used the rat neuronal cell line, PC12, in combination with analysis of SYBR staining and immuno-northern blotting using anti-1-methyladenosine antibody, which detects 1-methyladenosine (m

Topics: Adenosine; Animals; Biomarkers; Cell Survival; Glucose; Hypoxia; Ischemia; Neurons; Oxygen; PC12 Cells; Rats; Reperfusion Injury; Ribonuclease, Pancreatic; RNA, Transfer; Stress, Physiological; Stroke

Ischemic injuries permanently affect kidney tissue and challenge cell viability, promoting inflammation and fibrogenesis. Ischemia results in nutrient deprivation, which triggers endoplasmic reticulum stress, ultimately resulting in the unfolded protein response (UPR). The aim of this study was to test whether the UPR could promote an angiogenic response independently of the HIF-1α pathway during ischemic stress in the human kidney epithelium. Glucose deprivation induced the secretion of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and angiogenin (ANG) in human kidney epithelial cells independently of HIF-1α. Glucose deprivation, but not hypoxia, triggered endoplasmic reticulum stress and activated the UPR. RNA interference-mediated inhibition of the gene encoding the kinase PERK decreased VEGFA and bFGF expression, but neither gene was affected by the inhibition of IRE1α or ATF6. Furthermore, we show that the expression of angiogenin, which inhibits protein synthesis, is regulated by both IRE1α and PERK, which could constitute a complementary function of the UPR in the repression of translation. In a rat model of acute ischemic stress, we show that the UPR is activated in parallel with VEGFA, bFGF, and ANG expression and independently of HIF-1α.

Topics: Activating Transcription Factor 6; Animals; Cell Line; eIF-2 Kinase; Endoribonucleases; Epithelium; Fibroblast Growth Factor 2; Gene Expression Regulation; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemia; Kidney; Male; Membrane Proteins; Neovascularization, Pathologic; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Ribonuclease, Pancreatic; Stress, Physiological; Unfolded Protein Response; Vascular Endothelial Growth Factor A

The article contains experimental data on angiogenesis stimulated by plasmid containing the angiogenin gene. After the introduction of the gene construction, the number of capillars in the chorion-allantois membrane increases 2 to 3 times; in an ischemized limb of a rat it increases by 20 to 30%. Intramuscular administration of genetic engineering construction to patients with chronic lower limb ischemia improved the patients' condition, consisting in an increase in painless walking distance and ankle-brachial index, as well as in trophic defect healing and the betterment of muscular perfusion. Positive effects were noted after 2 to 4 weeks of treatment and remained during 6 to 24 months. There were no side-effects, except low grade fever during 1 to 2 days.

Topics: Adenoviridae; Adult; Aged; Animals; Chick Embryo; Chronic Disease; Data Interpretation, Statistical; Disease Models, Animal; Female; Fibroblast Growth Factors; Follow-Up Studies; Genetic Engineering; Genetic Vectors; Humans; Ischemia; Leg; Male; Middle Aged; Neovascularization, Physiologic; Plasmids; Rats; Rats, Wistar; Ribonuclease, Pancreatic; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A

The paper presents a new approach to management of lower limb critical ischemia which implements recent advances in molecular biology and genetic engineering technologies. A new original compound incorporating angiogenin gene was developed to activate neoangiogenesis processes after injection into living tissues. Experimental data evidence a potential efficacy of new method for complex management of critical ischemia.

Topics: Animals; Chick Embryo; Chronic Disease; DNA, Recombinant; Genetic Vectors; Ischemia; Lower Extremity; Male; Neovascularization, Physiologic; Plasmids; Protein Engineering; Rats; Rats, Wistar; Ribonuclease, Pancreatic; Vascular Surgical Procedures

Elevation of maternal serum alpha-fetoprotein in the second trimester is associated with poor pregnancy outcome, including fetal death, preterm delivery, and fetal growth restriction. We hypothesized that placental ischemia may be the common underlying pathogenesis of these outcomes. Thus we tested angiogenin, a potent inducer of neovascularization, in midtrimester amniotic fluid of patients with elevated maternal serum alpha-fetoprotein values to determine whether alpha-fetoprotein elevation is due to ischemia with subsequent stimulation of angiogenesis.. In this case-control study, patients with elevated maternal serum alpha-fetoprotein levels (> or = 2.0 multiples of the median, n = 9) at triple screen were matched with two controls (n = 18) on the basis of year of amniocentesis and maternal age, race, and parity. The median elevation of maternal serum alpha-fetoprotein in the study population was 4.01 multiples of the median (range 2.65 to 7.24 multiples of the median). Inclusion criteria were (1) singleton gestation, (2) no evidence of fetal structural or chromosomal anomalies, and (3) genetic amniocentesis. Amniotic fluid was immunoassayed for angiogenin (Quantikine, R&D Systems; sensitivity 0.026 ng/ml, interassay and intraassay coefficients of variation 4.6% and 2.9%, respectively). Statistical analysis included one-way analysis of variance and regression with p < 0.05 significant. Angiogenin and maternal serum alpha-fetoprotein values were normalized with use of natural log transformation for statistical analysis.. Angiogenin values were significantly elevated in patients with high maternal serum alpha-fetoprotein levels (median 31.1 [range 9.2 to 54.6] vs 17.1 [range 9.0 to 29.2] ng/ml, p = 0.02). Mean gestational age at sampling, maternal age, and year of amniocentesis were not significantly different between the study and control groups (each p > 0.05). As anticipated, there was a significant increase in preterm deliveries and small-for-gestational-age neonates in the patients with elevated maternal serum alpha-fetoprotein levels (each p < 0.01).. Midtrimester amniotic fluid angiogenin levels are significantly elevated in patients with elevated midtrimester maternal serum alpha-fetoprotein levels. Because angiogenin is a known marker of tissue ischemia, resulting in neovascularization, we hypothesize that elevation of maternal serum alpha-fetoprotein levels at triple screen is due to placental ischemia.

Topics: Adult; alpha-Fetoproteins; Case-Control Studies; Female; Humans; Infant, Newborn; Ischemia; Neovascularization, Physiologic; Placenta; Pregnancy; Pregnancy Trimester, Second; Proteins; Ribonuclease, Pancreatic