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1.
Gene Ther ; 29(10-11): 643-652, 2022 11.
Article in English | MEDLINE | ID: mdl-35132204

ABSTRACT

Therapeutic angiogenesis induced by gene therapy is a promising approach to treat patients suffering from severe coronary artery disease. In small experimental animals, adeno-associated viruses (AAVs) have shown good transduction efficacy and long-term transgene expression in heart muscle and other tissues. However, it has been difficult to achieve cardiac-specific angiogenic effects with AAV vectors. We tested the hypothesis whether AAV2 gene transfer (1 × 1013 vg) of vascular endothelial growth factor B (VEGF-B186) together with immunosuppressive corticosteroid treatment can induce long-term cardiac-specific therapeutic effects in the porcine ischemic heart. Gene transfers were delivered percutaneously using direct intramyocardial injections, improving targeting and avoiding direct contact with blood, thus reducing the likelihood of immediate immune reactions. After 1- and 6-month time points, the capillary area was analyzed, myocardial perfusion reserve (MPR) was measured with radiowater positron emission tomography ([15O]H2O-PET), and fluorodeoxyglucose ([18F]FDG) uptake was used to evaluate myocardial viability. Clinical chemistry and immune responses were analyzed using standard methods. After 1- and 6-month follow-up, AAV2-VEGF-B186 gene transfer failed to induce angiogenesis and improve myocardial perfusion and viability. Here, we show that inflammatory responses attenuated the therapeutic effect of AAV2 gene transfer by significantly reducing successful transduction and long-term gene expression despite the efforts to reduce the likelihood of immune reactions and the use of targeted local gene transfer methods.


Subject(s)
Genetic Vectors , Vascular Endothelial Growth Factor B , Animals , Swine , Vascular Endothelial Growth Factor B/genetics , Genetic Vectors/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/therapeutic use , Dependovirus/genetics , Genetic Therapy/methods , Myocardium
2.
Mol Biol Rep ; 48(6): 5347-5353, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34213709

ABSTRACT

Radiolabeled RGD peptides targeting expression of αvß3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvß3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.


Subject(s)
Acetates/pharmacokinetics , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Neovascularization, Physiologic/physiology , Oligopeptides/pharmacokinetics , Acetates/pharmacology , Angiogenesis Inducing Agents/pharmacology , Cell Culture Techniques, Three Dimensional/methods , Cell Line, Tumor , Endothelial Cells , Gallium Radioisotopes , Heterocyclic Compounds, 1-Ring/pharmacology , Humans , Integrin alphaVbeta3/metabolism , Isotope Labeling/methods , Models, Biological , Neovascularization, Physiologic/drug effects , Oligopeptides/pharmacology , Tissue Distribution
3.
J Nucl Cardiol ; 28(4): 1271-1280, 2021 08.
Article in English | MEDLINE | ID: mdl-31317328

ABSTRACT

BACKGROUND: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI). METHODS AND RESULTS: Pigs underwent resting [15O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively. CONCLUSIONS: Our results indicate that resting MBF, PTF, and PTI based on [15O]water PET perfusion imaging are useful for the assessment of myocardial viability.


Subject(s)
Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Positron-Emission Tomography , Animals , Coronary Circulation , Disease Models, Animal , Myocardial Infarction/physiopathology , Oxygen Radioisotopes , Predictive Value of Tests , ROC Curve , Swine , Tissue Survival
4.
J Transl Med ; 15(1): 144, 2017 06 19.
Article in English | MEDLINE | ID: mdl-28629432

ABSTRACT

BACKGROUND: Radiolabeled RGD peptides detect αvß3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvß3 integrin is expressed in viable ischemic or injured myocardium. METHODS: We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. RESULTS: Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvß3 integrin that was expressed in the injured myocardial areas. CONCLUSIONS: Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvß3 integrin expression associated with repair of recent myocardial injury.


Subject(s)
Acetates/chemistry , Gallium Radioisotopes/chemistry , Heterocyclic Compounds, 1-Ring/chemistry , Integrin alphaVbeta3/metabolism , Myocardial Ischemia/diagnostic imaging , Oligopeptides/chemistry , Positron-Emission Tomography , Acetates/pharmacokinetics , Animals , Autoradiography , Coronary Circulation , Gallium Radioisotopes/pharmacokinetics , Heterocyclic Compounds, 1-Ring/pharmacokinetics , Kinetics , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocardium/pathology , Oligopeptides/pharmacokinetics , Sus scrofa , Tissue Distribution
5.
Epilepsy Res ; 100(1-2): 80-92, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22348791

ABSTRACT

The central histaminergic neuron system is an important regulator of activity stages such as arousal and sleep. In several epilepsy models, histamine has been shown to modulate epileptic activity and histamine 1 (H1) receptors seem to play a key role in this process. However, little is known about the H1 receptor-mediated seizure regulation during the early postnatal development, and therefore we examined differences in severity of kainic acid (KA)-induced status epilepticus (SE) and consequent neuronal damage in H1 receptor knock out (KO) and wild type (WT) mice at postnatal days 14, 21, and 60 (P14, P21, and P60). Our results show that in P14 H1 receptor KO mice, SE severity and neuronal damage were comparable to those of WT mice, whereas P21 KO mice had significantly decreased survival, more severe seizures, and enhanced neuronal damage in various brain regions, which were observed only in males. In P60 mice, SE severity did not differ between the genotypes, but in KO group, neuronal damage was significantly increased. Our results suggest that H1 receptors could contribute to regulation of seizures and neuronal damage age-dependently thus making the histaminergic system as a challenging target for novel drug design in epilepsy.


Subject(s)
Neurons/pathology , Receptors, Histamine H1/deficiency , Status Epilepticus/metabolism , Status Epilepticus/pathology , Age Factors , Animals , Disease Susceptibility/metabolism , Disease Susceptibility/pathology , Female , Kainic Acid/toxicity , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Receptors, Histamine H1/genetics , Receptors, Histamine H1/physiology , Status Epilepticus/chemically induced
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