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1.
Cells ; 9(2)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991811

RESUMO

: Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. METHODS: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. RESULTS: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2-34.9) vs. 12.6% (IQR 8.3-27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. CONCLUSION: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates.

2.
Pflugers Arch ; 472(1): 61-74, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31822999

RESUMO

Neuronal nitric oxide synthase (nNOS) is considered a regulator of Cav1.2 L-type Ca2+ channels and downstream Ca2+ cycling in the heart. The commonest view is that nitric oxide (NO), generated by nNOS activity in cardiomyocytes, reduces the currents through Cav1.2 channels. This gives rise to a diminished Ca2+ release from the sarcoplasmic reticulum, and finally reduced contractility. Here, we report that nNOS inhibitor substances significantly increase intracellular Ca2+ transients in ventricular cardiomyocytes derived from adult mouse and rat hearts. This is consistent with an inhibitory effect of nNOS/NO activity on Ca2+ cycling and contractility. Whole cell currents through L-type Ca2+ channels in rodent myocytes, on the other hand, were not substantially affected by the application of various NOS inhibitors, or application of a NO donor substance. Moreover, the presence of NO donors had no effect on the single-channel open probability of purified human Cav1.2 channel protein reconstituted in artificial liposomes. These results indicate that nNOS/NO activity does not directly modify Cav1.2 channel function. We conclude that-against the currently prevailing view-basal Cav1.2 channel activity in ventricular cardiomyocytes is not substantially regulated by nNOS activity and NO. Hence, nNOS/NO inhibition of Ca2+ cycling and contractility occurs independently of direct regulation of Cav1.2 channels by NO.

3.
J Thorac Cardiovasc Surg ; 158(6): 1543-1554.e8, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31753163

RESUMO

OBJECTIVE: Cardiac surgery demands highly effective cardioprotective regimens. We previously demonstrated improved cardioprotection with "polarized" compared with "depolarized" arrest. This study uses a clinically relevant porcine model of cardiopulmonary bypass to compare the efficacy of blood-based St Thomas' Hospital polarizing cardioplegia (STH-Pol-B) with blood-based St Thomas' Hospital hyperkalemic cardioplegia (STH2-B). METHODS: Pigs were monitored and subjected to normothermic cardiopulmonary bypass, cardiac arrest via antegrade cold (4°C) blood cardioplegia (STH2-B, control group: n = 6 or STH-Pol-B, study group: n = 7), and global ischemia (60 minutes) followed by on-pump reperfusion (60 minutes) and subsequent off-pump reperfusion (90 minutes). At termination, tissue samples were taken for analysis of high-energy phosphates, ultrastructure, and microRNAs. The primary endpoint of this study was creatine kinase-muscle/brain release during reperfusion. RESULTS: Creatine kinase-muscle/brain was comparable in both groups. After pigs were weaned from cardiopulmonary bypass, hemodynamic parameters such as mean arterial pressure (P = .007), left ventricular systolic pressure (P < .001), external heart work (P = .012), stroke volume (P = .015), as well as dp/dtmax (P = .027), were improved with polarizing cardioplegia. Wedge pressure was significantly lower in the study group (P < .01). Energy charge was comparable between groups. MicroRNA-708-5p was significantly lower (P = .019) and microRNA-122 expression significantly (P = .046) greater in STH-Pol-B hearts. CONCLUSIONS: Polarized cardiac arrest offers similar myocardial protection and enhances functional recovery in a porcine model of cardiopulmonary bypass. Differential expression of microRNAs may indicate possible new ischemia-reperfusion markers. These results confirm the noninferiority and potential of polarized versus depolarized arrest.

4.
Front Neurosci ; 13: 772, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396044

RESUMO

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve - a powerful entrance to the brain - affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects - a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

6.
Front Neurosci ; 13: 854, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447643

RESUMO

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

7.
EuroIntervention ; 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31235459

RESUMO

INTRODUCTION: Alternative approaches for mitral valve repair are being constantly developed. Even though the safety of these devices has been extensively assessed in healthy animals before approval for first-in-man studies, often the efficacy of these new devices has been hardly challenged in vivoin the setting of MR. Therefore, reliable and reproducible preclinical animal models of MR are crucial to allow not only the safety assessment but also the efficacy evaluation of these novel approaches.

8.
Int J Biol Macromol ; 136: 847-858, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226374

RESUMO

Roseroot (Rhodiola rosea L.) is a medicinal plant with adaptogenic properties and several pharmaceutically important metabolites. In this study, a full length cDNA encoding a UDPG gene of roseroot was identified, cloned and characterized. Its ORF (1425 bp) was transferred into E. coli, where the expression of the recombinant enzyme was confirmed. To monitor the enzyme activity, 3 precursors (tyramine, 4-hydroxyphenylpyruvate & tyrosol) of salidroside biosynthesis pathway were added to roseroot callus cultures and samples were harvested after 1, 6, 12, 24, 48 & 96 h. Along with the controls (without precursor feeding), each sample was subjected to HPLC and qRT-PCR for phytochemical and relative UDP-glycosyltransferase gene expression analysis, respectively. The HPLC analysis showed that the salidroside content significantly increased; reaching 0.5% of the callus dry weight (26-fold higher than the control) after 96 h when 2 mM tyrosol was given to the media. The expression of the UDP-glycosyltransferase increased significantly being the highest at 12 h after the feeding. The effect of tyramine and 4-hydroxyphenylpyruvate was not as pronounced as of tyrosol. Here, we introduce a R. rosea specific UDPG gene and its expression pattern after biotransformation of intermediate precursors in in vitro roseroot callus cultures.


Assuntos
Regulação da Expressão Gênica de Plantas , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Rhodiola/enzimologia , Rhodiola/genética , Difosfato de Uridina/metabolismo , Biotransformação , Técnicas de Cultura , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/metabolismo , Filogenia , Rhodiola/crescimento & desenvolvimento
11.
J Hypertens ; 37(9): 1861-1870, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30950975

RESUMO

BACKGROUND: Tenascin C (TN-C) is considered to play a pathophysiological role in maladaptive left ventricular remodeling. Yet, the mechanism underlying TN-C-dependent cardiac dysfunction remains elusive. METHOD: The present study was designed to investigate the effect of hypoxia and hypertrophic stimuli on TN-C expression in H9c2 cells and its putative regulation by epigenetic mechanisms, namely DNA promoter methylation and microRNAs. In addition, rats subjected to myocardial infarction (MI) were investigated. H9c2 cells were subjected to oxygen and glucose deprivation; incubated with angiotensin II (Ang II); or human TN-C (hTN-C) purified protein. Hypertrophic and fibrotic markers, TN-C promoter methylation as well as mir-335 expression were assessed by reverse transcription and quantitative polymerase chain reaction while TN-C protein levels were assessed by ELISA. RESULTS: Tn-C mRNA expression was markedly increased by both oxygen and glucose deprivation and Ang II (P < 0.01, respectively). In addition, Ang-II-dependent TN-C upregulation was explained by reduced promoter methylation (P < 0.05). Cells treated with hTN-C displayed upregulation of Bnp, Mmp2, ß-Mhc, integrin α6 and integrin ß1. Furthermore, hTN-C treated cells showed a significant reduction in adenosine monophosphate and adenosine triphosphate levels. In vivo, plasma and myocardial TN-C levels were increased 7 days post MI (P < 0.05, respectively). This increment in TN-C was accompanied by upregulation of mir-335 (P < 0.01). In conclusion, both hypoxic and hypertrophic stimuli lead to epigenetically driven TN-C upregulation and subsequent impairment of cellular energy metabolism in cardiomyoblasts. CONCLUSION: These findings might enlighten our understanding on maladaptive left ventricular remodeling and direct towards a strong involvement of TN-C.

12.
Int J Cardiol ; 285: 72-79, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30904281

RESUMO

AIMS: Remote ischemic conditioning (RIC) is considered a potential clinical approach to reduce myocardial infarct size and ameliorate adverse post-infarct left ventricular (LV) remodeling, however the mechanisms are unknown. The aim was to clarify the impact of RIC on Neuregulin-1 (NRG-1)/ErbBs expression, inflammation and LV hemodynamic function. METHODS AND RESULTS: Male Sprague-Dawley rats were subjected to 30 min occlusion of the left coronary artery (LCA) followed by 2 weeks of reperfusion and separated into three groups: (1) sham operated (without LCA occlusion); (2) Myocardial ischemia/reperfusion (MIR) and (3) remote ischemic perconditioning group (MIR + RIPerc). Cardiac structural and functional changes were evaluated by echocardiography and on the isolated working heart system. The level of H3K4me3 at the NRG-1 promoter, and both plasma and LV tissue levels of NRG-1 were assessed. The expression of pro-inflammatory cytokines, ECM components and ErbB receptors were assessed by RT-qPCR. MIR resulted in a significant decrease in LV function and enlargement of LV chamber. This was accompanied with a decrease in the level of H3K4me3 at the NRG-1 promoter. Consequently NRG-1 protein levels were reduced in the infarcted myocardium. Subsequently, an upregulated influx of CD68+ macrophages, high expression of MMP-2 and -9 as well as an increase of IL-1ß, TLR-4, TNF-α, TNC expression were observed. In contrast, RIPerc significantly decreased inflammation and improved LV function in association with the enhancement of NRG-1 levels and ErbB3 expression. CONCLUSIONS: These findings may reveal a novel anti-remodeling and anti-inflammatory effect of RIPerc, involving activation of NRG-1/ErbB3 signaling.

13.
Int J Mol Sci ; 20(6)2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901815

RESUMO

Although reperfusion therapy has improved outcomes, acute myocardial infarction (AMI) is still associated with both significant mortality and morbidity. Once irreversible myocardial cell death due to ischemia and reperfusion sets in, scarring leads to reduction in left ventricular function and subsequent heart failure. Regenerative cardiovascular medicine experienced a boost in the early 2000s when regenerative effects of bone marrow stem cells in a murine model of AMI were described. Translation from an animal model to stem cell application in a clinical setting was rapid and the first large trials in humans suffering from AMI were conducted. However, high initial hopes were early shattered by inconsistent results of randomized clinical trials in patients suffering from AMI treated with stem cells. Hence, we provide an overview of both basic science and clinical trials carried out in regenerative cardiovascular therapies. Possible pitfalls in specific cell processing techniques and trial design are discussed as these factors influence both basic science and clinical outcomes. We address possible solutions. Alternative mechanisms and explanations for effects seen in both basic science and some clinical trials are discussed here, with special emphasis on paracrine mechanisms via growth factors, exosomes, and microRNAs. Based on these findings, we propose an outlook in which stem cell therapy, or therapeutic effects associated with stem cell therapy, such as paracrine mechanisms, might play an important role in the future. Optimizing stem cell processing and a better understanding of paracrine signaling as well as its effect on cardioprotection and remodeling after AMI might improve not only AMI research, but also our patients' outcomes.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Medicina Regenerativa , Transplante de Células-Tronco , Células-Tronco , Animais , Biomarcadores , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Reprogramação Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Exossomos/metabolismo , Regulação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos , MicroRNAs/genética , Miocárdio/citologia , Miocárdio/metabolismo , Medicina Regenerativa/história , Medicina Regenerativa/métodos , Transplante de Células-Tronco/história , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Células-Tronco/metabolismo , Pesquisa Médica Translacional
14.
Exp Gerontol ; 119: 193-202, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30763602

RESUMO

The aim of this study was to describe the potential associations of the expression of matricellular components in adverse post-infarction remodeling of the geriatric heart. In male geriatric (OM, age: 18 months) and young (YM, age: 11 weeks) OF1 mice myocardial infarction (MI) was induced by permanent ligation of the left anterior descending coronary artery. Cardiac function was evaluated by MRI. Plasma and myocardial tissue samples were collected 3d, 7d, and 32d post-MI. Age and MI were associated with impaired cardiac function accompanied by left-ventricular (LV) dilatation. mRNA expression of MMP-2 (7d: p < 0.05), TIMP-1 (7d: p < 0.05), TIMP-2 (7d: p < 0.05), Collagen-1 (3d and 7d: p < 0.05) and Collagen-3 (7d: p < 0.05) in LV non-infarcted myocardium was significantly higher in YM than in OM after MI. MMP-9 activity in plasma was increased in OM after MI (3d: p < 0.01). Tenascin-C protein levels assessed by ELISA were decreased in OM as compared to YM after MI in plasma (3d: p < 0.001, 7d: p < 0.05) and LV non-infarcted myocardium (7d: p < 0.01). Dysregulation in ECM components in non-infarcted LV might be associated and contribute to adverse LV remodeling and impaired cardiac function. Thus, targeting ECM might be a potential therapeutic approach to enhance cardiac function in geriatric patients following MI.

15.
J Clin Invest ; 129(2): 531-545, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422822

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder characterized by accelerated cardiovascular disease with extensive fibrosis. It is caused by a mutation in LMNA leading to expression of truncated prelamin A (progerin) in the nucleus. To investigate the contribution of the endothelium to cardiovascular HGPS pathology, we generated an endothelium-specific HGPS mouse model with selective endothelial progerin expression. Transgenic mice develop interstitial myocardial and perivascular fibrosis and left ventricular hypertrophy associated with diastolic dysfunction and premature death. Endothelial cells show impaired shear stress response and reduced levels of endothelial nitric oxide synthase (eNOS) and NO. On the molecular level, progerin impairs nucleocytoskeletal coupling in endothelial cells through changes in mechanoresponsive components at the nuclear envelope, increased F-actin/G-actin ratios, and deregulation of mechanoresponsive myocardin-related transcription factor-A (MRTFA). MRTFA binds to the Nos3 promoter and reduces eNOS expression, thereby mediating a profibrotic paracrine response in fibroblasts. MRTFA inhibition rescues eNOS levels and ameliorates the profibrotic effect of endothelial cells in vitro. Although this murine model lacks the key anatomical feature of vascular smooth muscle cell loss seen in HGPS patients, our data show that progerin-induced impairment of mechanosignaling in endothelial cells contributes to excessive fibrosis and cardiovascular disease in HGPS patients.


Assuntos
Células Endoteliais/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Lamina Tipo A/biossíntese , Mecanotransdução Celular , Miocárdio/metabolismo , Elementos de Resposta , Transativadores/metabolismo , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Lamina Tipo A/genética , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo III/biossíntese , Óxido Nítrico Sintase Tipo III/genética , Transativadores/genética
16.
JACC Basic Transl Sci ; 3(4): 450-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175269

RESUMO

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

17.
Eur Heart J Acute Cardiovasc Care ; : 2048872618784150, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29911392

RESUMO

BACKGROUND: The efficacy of remote ischaemic conditioning in clinical trials of ST-segment elevation myocardial infarction (STEMI) or elective percutaneous coronary intervention is controversial. We aimed to systematically review and meta-analyse whether remote ischaemic conditioning reduces myocardial damage in those patients. METHODS: We searched PubMed, Embase and Web of Science from inception until December 2017 for randomised clinical trials evaluating remote ischaemic conditioning versus a control group. Two independent reviewers extracted data of 23 trials (2118 patients with STEMI; 2048 patients undergoing elective percutaneous coronary intervention) which were meta-analysed using random-effects models. RESULTS: Remote ischaemic conditioning reduced infarct size in STEMI patients when assessed by imaging (mean difference of infarct size as percentage of left ventricle -2.43, 95% confidence interval (CI) -4.37 to -0.48; P=0.01; I2=44%; n=925) or biomarkers related to myocardial injury (peak values of cardiac biomarker release reported as standardised mean difference -0.19, 95% CI -0.37 to -0.02; P=0.03; I2=58%; n=1483) and increased myocardial salvage index (mean difference 0.07, 95% CI 0.01 to 0.13; P=0.02; I2=49%; n= 636). Left ventricular ejection fraction was increased when assessed during the first days after STEMI (mean difference 1.53, 95% CI 0.23 to 2.83; P=0.02; I2=28%; n=1192). Remote ischaemic conditioning had no influence on biomarker values after elective percutaneous coronary intervention (standardised mean difference 0.06, 95% CI -0.17 to 0.30; P=0.59). CONCLUSIONS: Despite a statistically significant reduction of myocardial damage in STEMI patients, the magnitude of the reduction was small and a significant impact on clinical events is unlikely. With respect to elective percutaneous coronary intervention, remote ischaemic conditioning had no influence on myocardial injury and its use is not supported by our analysis.

18.
Shock ; 49(5): 556-563, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29658909

RESUMO

BACKGROUND: The noble gas argon induces cardioprotection in a rabbit model of myocardial ischemia and reperfusion. However, no studies in human primary cells or subjects have been performed so far. We used human cardiac myocyte-like progenitor cells (HCMs) to investigate the protective effect on the cellular level. METHODS: HCMs were pretreated with 30% or 50% argon before oxygen-glucose deprivation (OGD) and reperfusion. We evaluated apoptotic states by flow cytometry and the activation of mitogen-activated protein kinase (MAPKs) members extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 MAPkinase, and protein kinase B (Akt) by Westernblot analysis and by activity assays of downstream transcription factors. Specific inhibitors were used to proof a significant participation of these pathways in the protection by argon. Beneficial effects were further assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay, lactate dehydrogenase (LDH), mitochondrial deoxyribonucleic acid (mtDNA), and cytokine release. RESULTS: Pretreatment with 30% or 50% argon for 90 min before OGD resulted in a significant protection of HCMs against apoptosis. This effect was reversed by the application of MAPK and Akt inhibitors during argon exposure. Argon 30% reduced the release of LDH by 33% and mtDNA by 45%. The release of interleukin 1ß was reduced by 44% after OGD and more than 90% during reperfusion. CONCLUSIONS: Pretreatment with argon protects HCMs from apoptosis under ischemic conditions via activation of Akt, Erk, and biphasic regulation of JNK. Argon gas is cheap and easily administrable, and might be a novel therapy to reduce myocardial ischemia-reperfusion injury.


Assuntos
Argônio/farmacologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Citometria de Fluxo , Humanos , Marcação In Situ das Extremidades Cortadas , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , L-Lactato Desidrogenase/metabolismo , Coelhos , Transdução de Sinais/efeitos dos fármacos
19.
Eur J Cardiothorac Surg ; 54(3): 539-546, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29547976

RESUMO

OBJECTIVES: Previous studies demonstrated that preconditioning with argon gas provided a marked reduction in inflammation and apoptosis and increased myocardial contractility in the setting of acute myocardial ischaemia-reperfusion (IR). There is substantial evidence that myocardial IR injury following cardioplegic arrest is associated with the enhancement of apoptosis and inflammation, which is considered to play a role in cardiac functional impairment. Therefore, the present study was designed to clarify whether preconditioning with argon gas enhances recovery of cardiac function following cardioplegic arrest. METHODS: Sprague-Dawley rats were anaesthetized and ventilated and allocated to (i) the control group (control IR, n = 10) and (ii) the in vivo group (argon IR), which received 3 cycles of argon (50% argon, 21% oxygen and 29% nitrogen, n = 10) administered for 5 min interspersed with 5 min of a gas mixture (79% nitrogen and 21% oxygen). The hearts were excised and then evaluated in an erythrocyte-perfused isolated working heart system. Cold ischaemia (4°C) for 60 min was induced by histidine-tryptophan-ketoglutarate cardioplegia, followed by 40 min of reperfusion. Cardiac functional parameters were assessed. In left ventricular tissue samples, the expressions of extracellular-regulated kinase (ERK1/2), AKT serine/threonine kinase (Akt), jun N-terminal kinase (JNK), endothelial nitric oxide synthase (eNOS) and HMGB1: high-mobility group box 1 (HMGB1) protein were assessed by western blot, and high-energy phosphates were evaluated by high-performance liquid chromatography. RESULTS: At the end of reperfusion, the rats preconditioned with argon showed significantly enhanced recovery of cardiac output (101 ± 6% vs 87 ± 11%; P < 0.01), stroke volume (94 ± 4% vs 80 ± 11%; P = 0.001), external heart work (100 ± 6% vs 81 ± 13%; P < 0.001) and coronary flow (90 ± 13% vs 125 ± 21%; P < 0.01) compared with the control IR group. These results were accompanied by a significant increase in the levels of myocardial phosphocreatine (23.71 ± 2.07 µmol/g protein vs the control IR group, 13.50 ± 4.75; P = 0.001) and maintained adenosine triphosphate levels (13.62 ±1.89 µmol/g protein vs control IR group adenosine triphosphate: 10.08 ± 1.94 µmol/g; P = 0.017). Additionally, preconditioning with argon markedly reduced the activation of JNK (0.11 ± 0.01 vs 0.25 ± 0.03; P = 0.005) and the expression of HMGB1 protein (0.52 ± 0.04 vs 1.5 ± 0.10; P < 0.001) following reperfusion. CONCLUSIONS: Preconditioning with argon enhanced cardiac functional recovery in rat hearts arrested with histidine-tryptophan-ketoglutarate cardioplegia, thereby representing a potential novel cardioprotective approach in cardiac surgery.


Assuntos
Argônio/farmacologia , Soluções Cardioplégicas/farmacologia , Cardiotônicos/farmacologia , Parada Cardíaca Induzida/métodos , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Administração por Inalação , Animais , Argônio/administração & dosagem , Soluções Cardioplégicas/administração & dosagem , Cardiotônicos/administração & dosagem , Coração/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
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