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1.
Aging Cell ; 22(3): e13768, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36756698

RESUMO

Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.


Assuntos
Proteínas de Ligação a DNA , Insuficiência Cardíaca , Camundongos , Animais , Humanos , Proteínas de Ligação a DNA/metabolismo , Miócitos Cardíacos/metabolismo , Reparo do DNA/genética , Dano ao DNA/genética , Insuficiência Cardíaca/genética , Endonucleases
2.
Sci Rep ; 10(1): 2173, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034227

RESUMO

Extensive application of coronary intravascular procedures has led to the increased need of understanding the injury inflicted to the coronary arterial wall. We aimed to investigate acute and prolonged coronary endothelial injury as a result of guidewire use, repeated intravascular imaging and stenting. These interventions were performed in swine (N = 37) and injury was assessed per coronary segment (n = 81) using an Evans Blue dye-exclusion-test. Scanning electron microscopy and light microscopy were then used to visualize the extent and nature of acute (<4 hours) and prolonged (5 days) endothelial injury. Guidewire and imaging injury was mainly associated with denudation and returned to control levels at 5 days. IVUS and OCT combined (Evans Blue staining 28 ± 16%) did not lead to more acute injury than IVUS alone (33 ± 15%). Stent placement caused most injury (85 ± 4%) and despite early stent re-endothelialization at 5 days, the endothelium proved highly permeable (97 ± 4% at 5 days; p < 0.001 vs acute). Imaging of in-stent neointima at 28 days after stent placement did not lead to neointimal rupture. Guidewire, IVUS and OCT induce acute endothelial cell damage, which does not increase during repeated imaging, and heals within 5 days. Interestingly, endothelial permeability increases 5 days post stenting despite near complete re-endothelialization.


Assuntos
Vasos Coronários/lesões , Stents Farmacológicos/efeitos adversos , Neointima/patologia , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias/patologia , Animais , Neointima/diagnóstico por imagem , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/métodos , Complicações Pós-Operatórias/etiologia , Suínos , Tomografia de Coerência Óptica/efeitos adversos , Tomografia de Coerência Óptica/métodos , Ultrassonografia de Intervenção/efeitos adversos , Ultrassonografia de Intervenção/métodos
3.
Arterioscler Thromb Vasc Biol ; 39(11): 2338-2352, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31554418

RESUMO

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiles were determined. Approach and Results: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. Coronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference was observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%-34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, 69% [57%-77%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly diseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion chromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine-1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory techniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular LDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3-1.9] versus 0.8 [0.6-0.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and sphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. CONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to the distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet start. A similar LDL profile was detected in patients with homozygous FH.


Assuntos
LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/patologia , Placa Aterosclerótica/sangue , Placa Aterosclerótica/patologia , Animais , LDL-Colesterol/classificação , Dieta Aterogênica , Modelos Animais de Doenças , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico por imagem , Masculino , Placa Aterosclerótica/diagnóstico por imagem , Índice de Gravidade de Doença , Esfingolipídeos/sangue , Suínos
4.
Am J Physiol Lung Cell Mol Physiol ; 315(6): L951-L964, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30260284

RESUMO

Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor Nω-nitro-l-arginine methyl ester until 2 wk before the end of study. Swine were subjected to exercise, and the pulmonary vasculature was investigated by hemodynamic, histological, quantitative PCR, and myograph experiments. In swine with CTEPH, the increased right-ventricular afterload, decreased cardiac index, and mild ventilation-perfusion-mismatch were exacerbated during exercise. Pulmonary microvascular remodeling was evidenced by increased muscularization, which was accompanied by an increased maximal vasoconstriction. Although ET-1-induced vasoconstriction was increased in CTEPH pulmonary small arteries, the ET-1 sensitivity was decreased. Moreover, the contribution of the ETA receptor to ET-1 vasoconstriction was increased, whereas the contribution of the ETB receptor was decreased and the contribution of Rho-kinase was lost. A reduction in endogenous NO production was compensated in part by a decreased phosphodiesterase 5 (PDE5) activity resulting in an apparent increased NO sensitivity in CTEPH pulmonary small arteries. These findings suggest that pulmonary microvascular remodeling with a reduced activity of PDE5 and Rho-kinase may contribute to the lack of therapeutic efficacy of PDE5 inhibitors and Rho-kinase inhibitors in CTEPH.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Pulmão/fisiopatologia , Microvasos/fisiopatologia , Embolia Pulmonar/fisiopatologia , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Endotelina-1/metabolismo , Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Microvasos/metabolismo , Óxido Nítrico/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/fisiologia , Embolia Pulmonar/metabolismo , Suínos , Vasoconstrição/fisiologia , Quinases Associadas a rho/metabolismo
5.
PLoS One ; 12(9): e0183419, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898243

RESUMO

BACKGROUND: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. AIM: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. METHODS: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. RESULTS: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. CONCLUSION: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.


Assuntos
Implantes Absorvíveis/efeitos adversos , Aterosclerose/etiologia , Aterosclerose/patologia , Diabetes Mellitus/patologia , Neointima/patologia , Alicerces Teciduais/efeitos adversos , Animais , Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Biomarcadores , Biópsia , Colágeno/metabolismo , Vasos Coronários/patologia , Diabetes Mellitus/metabolismo , Modelos Animais de Doenças , Masculino , Neointima/metabolismo , Suínos , Tomografia de Coerência Óptica
7.
Basic Res Cardiol ; 110(5): 508, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26306761

RESUMO

Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p < 0.05), whereas systemic circulating plasma levels of TNFα and IL6 were not affected. The degree of cardioprotection could not be explained by the VNS-induced bradycardia or the VNS-induced decrease in the double product of heart rate and left ventricular systolic pressure. In the presence of NO-synthase inhibitor LNNA, VNS no longer attenuated infarct size and area of no-reflow, which was paralleled by similarly unaffected regional leukocyte infiltration. In conclusion, VNS is a promising novel adjunctive therapy that limits reperfusion injury in a large animal model of acute myocardial infarction.


Assuntos
Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estimulação do Nervo Vago/métodos , Animais , Modelos Animais de Doenças , Feminino , Masculino , Sus scrofa
8.
Am J Physiol Heart Circ Physiol ; 309(3): H396-406, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26024685

RESUMO

Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-µm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.


Assuntos
Citocinas/sangue , Microesferas , Infarto do Miocárdio/tratamento farmacológico , Neovascularização Fisiológica , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Função Ventricular , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Microvasos/fisiologia , Poliésteres/química , Polietilenoglicóis/química , Suínos , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/farmacocinética
9.
JACC Cardiovasc Interv ; 8(15): 1990-1999, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26738671

RESUMO

OBJECTIVES: In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND: Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. METHODS: Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 µg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS: In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). CONCLUSIONS: During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion.


Assuntos
Adenosina/administração & dosagem , Oclusão Coronária/terapia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Reperfusão Miocárdica/efeitos adversos , Miocárdio/patologia , Fenômeno de não Refluxo/prevenção & controle , Animais , Circulação Coronária , Oclusão Coronária/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Hemodinâmica , Infusões Parenterais , Masculino , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fenômeno de não Refluxo/etiologia , Fenômeno de não Refluxo/patologia , Fenômeno de não Refluxo/fisiopatologia , Suínos , Fatores de Tempo
10.
Am J Physiol Heart Circ Physiol ; 305(7): H1104-10, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23873799

RESUMO

The objective of this study was to compare heart-specific fatty acid binding protein (hFABP) and high-sensitivity troponin I (hsTnI) via serial measurements to identify early time points to accurately quantify infarct size and no-reflow in a preclinical swine model of ST-elevated myocardial infarction (STEMI). Myocardial necrosis, usually confirmed by hsTnI or TnT, takes several hours of ischemia before plasma levels rise in the absence of reperfusion. We evaluated the fast marker hFABP compared with hsTnI to estimate infarct size and no-reflow upon reperfused (2 h occlusion) and nonreperfused (8 h occlusion) STEMI in swine. In STEMI (n = 4) and STEMI + reperfusion (n = 8) induced in swine, serial blood samples were taken for hFABP and hsTnI and compared with triphenyl tetrazolium chloride and thioflavin-S staining for infarct size and no-reflow at the time of euthanasia. hFABP increased faster than hsTnI upon occlusion (82 ± 29 vs. 180 ± 73 min, P < 0.05) and increased immediately upon reperfusion while hsTnI release was delayed 16 ± 3 min (P < 0.05). Peak hFABP and hsTnI reperfusion values were reached at 30 ± 5 and 139 ± 21 min, respectively (P < 0.05). Infarct size (containing 84 ± 0.6% no-reflow) correlated well with area under the curve for hFABP (r(2) = 0.92) but less for hsTnI (r(2) = 0.53). At 50 and 60 min reperfusion, hFABP correlated best with infarct size (r(2) = 0.94 and 0.93) and no-reflow (r(2) = 0.96 and 0.94) and showed high sensitivity for myocardial necrosis (2.3 ± 0.6 and 0.4 ± 0.6 g). hFABP rises faster and correlates better with infarct size and no-reflow than hsTnI in STEMI + reperfusion when measured early after reperfusion. The highest sensitivity detecting myocardial necrosis, 0.4 ± 0.6 g at 60 min postreperfusion, provides an accurate and early measurement of infarct size and no-reflow.


Assuntos
Circulação Coronária , Proteínas de Ligação a Ácido Graxo/sangue , Infarto do Miocárdio/terapia , Reperfusão Miocárdica/efeitos adversos , Miocárdio/metabolismo , Fenômeno de não Refluxo/etiologia , Troponina I/sangue , Animais , Benzotiazóis , Biomarcadores/sangue , Modelos Animais de Doenças , Feminino , Hemodinâmica , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Necrose , Fenômeno de não Refluxo/sangue , Fenômeno de não Refluxo/patologia , Fenômeno de não Refluxo/fisiopatologia , Valor Preditivo dos Testes , Fatores de Risco , Coloração e Rotulagem/métodos , Suínos , Sais de Tetrazólio , Tiazóis , Fatores de Tempo , Regulação para Cima
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