Ildiko Bock-Marquette - Academia.edu (original) (raw)

Papers by Ildiko Bock-Marquette

International Immunopharmacology

European Heart Journal, 2016

Circulation, 2014

Diabetes and hypercholesterolemia are two of the major risk factors for developing cardiovascular... more Diabetes and hypercholesterolemia are two of the major risk factors for developing cardiovascular disease, especially in combination with chronic myocardial ischemia it represents one of the most common causes of disability or death. New pro-angiogenic factors like Thymosin ß4 (Tß4), a small 4.9 kDa peptide influences cell motility and migration might be suitable for inducing therapeutic neovascularization in chronic myocardial ischemia a cardiovascular risk factors. Methods: Chronic ischemia was induced via reduction stent graft in the circumflex artery, leading to a total occlusion on day 28 (d28). Beside wildtyp animals (wt) ± high fat diet (hypercholesteric (hyp), choselsterol 78±1 wt vs 90±2 hyp), d iabetic transgenic pigs were used (increased blood glucose 305 ±12 mg/dL) . Regional application of rAAV Tß4 (5x10E12 viral particles, d28) was performed in wt, hyp and diabetic pigs respectively. Global myocardial function was obtained at day 28 and 56. Regional myocardial function...

Crimean-Congo hemorrhagic fever virus (CCHFV) is one of the prioritized diseases of World Health ... more Crimean-Congo hemorrhagic fever virus (CCHFV) is one of the prioritized diseases of World Health Organization, considering its potential to create a public health emergency and more importantly, the absence of efficacious drugs and/or vaccines regarding treatment. The highly lethal nature characteristic to CCHFV restricts research to BSL-4 laboratories, which complicates effective research and developmental strategies. In consideration of antiviral therapies, RNA interference can be used to suppress viral replication by targeting viral genes. RNA interference uses small interfering RNAs (siRNAs) to silence genes. The aim of our study was to design siRNAs that inhibit CCHFV replication and can serve as a basis for further antiviral therapies. A549 cells were infected with CCHFV after transfection with the siRNAs. Following 72 hours, nucleic acid from the supernatant was extracted for Droplet Digital PCR analysis. Among the investigated siRNAs we identified four effective candidates a...

Ticks and Tick-borne Diseases, 2019

Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne pathogen, which causes an increasi... more Crimean-Congo haemorrhagic fever virus (CCHFV) is a tick-borne pathogen, which causes an increasing number of severe infections in many parts of Africa, Asia and in Europe. The virus is primarily transmitted by ticks, however, the spectrum of natural hosts regarding CCHFV includes a wide variety of domestic and wild animals. Although the presence of CCHFV was hypothesized in Hungary, data in support of CCHFV prevalence has thus far, proven insufficient. In the present study, rodents belonging to four species, the yellow-necked mouse (Apodemus flavicollis), the striped field mouse (A. agrarius), the wood mouse (A. sylvaticus) and the bank vole (Myodes glareolus), were all systematically trapped in the Mecsek Mountain region (Southwest Hungary), from 2011 through 2013. Rodent sera were collected and screened for CCHFV antibodies with dot-blot pre-screening and immunofluorescence assay. Among the 2085 tested rodents, 20 (0.96%) were positive for IgG antibody against CCHFV. Seroprevalence was the highest (1.25%) in A. flavicollis serum samples. Distinctly, we now provide the first data regarding CCHFV occurrence and seroprevalence among wild rodents in Hungary. This observation represents a need for large-scale surveillance to effectively assess the enzootic background and the potential public health risk of CCHFV in Hungary.

Circulation, Oct 31, 2006

Journal of stem cells & regenerative medicine, 2007

Journal of Surgical Research, 2006

Introduction: Robotically-assisted minimally invasive mitral valve reconstruction has recently ga... more Introduction: Robotically-assisted minimally invasive mitral valve reconstruction has recently gained popularity. Initial reports suggest that this approach can be utilized with relative safety and efficacy. Direct comparisons with a traditional sternotomy approach have not yet been extensively explored. Methods: All mitral valve procedures performed by a single surgeon during a three year period of time were analyzed. (nϭ142) Patients requiring concomitant coronary artery bypass grafting or aortic valve surgery were subsequently excluded from analysis, as all of these patients were obligatorily approached via sternotomy (nϭ71). Six patients underwent right thoracotomy mitral valve procedures without robotic assistance and one patient in cardiogenic shock underwent emergent mitral valve reconstruction via sternotomy. Of the remaining 64 patients theoretically eligible for sternotomy or robotically-assisted minimally invasive surgery, 39 underwent sternotomy and 25 underwent right chest minimally invasive robotically-assisted surgery. Randomization between these two approaches would be almost impossible in the United States. The primary determinant for choice of approach was request of the referring physician or patient. Multiple perioperative outcomes were then compared. Results: Sternotomy and robotic patients exhibited equivalent preoperative characteristics. Robotic and sternotomy patients experienced equivalent degree of correction of mitral regurgitation in repairs and in need for replacement. Complex mitral valve repairs entailing leaflet resection and reapproximation, annular plication, sliding annuloplasty, chordal transfer, and GoreTex neochordal construction were successfully accomplished with the robotic system. Crossclamp and bypass times were longer in minimally invasive patients (110 vs 151min pϭ0.0015, 162 vs 239min pϽ0.001). Far greater robotic patients avoided any blood product transfusion 38% vs 15% and mean PRBC transfusion trended to a significantly lower amount among robotic patients (2.9 vs 4.8units pϭ0.06). Robotic patients experienced shorter mean length of postoperative hospitalization (7.1 vs 10.6 days pϭ0.039). There was one mortality among the sternotomy patients and no mortalities among the robotic patients. Conclusions: Patients can undergo mitral valve reconstruction with minimally invasive robotic assistance, avoid a sternotomy, require less blood product transfusion, and experience shorter hospitalization.

Cardiovascular Research, 2010

Cardiovascular Research, 2012

Fibroblast growth factors (FGFs) and their receptors play an important role during embryonic indu... more Fibroblast growth factors (FGFs) and their receptors play an important role during embryonic induction and patterning, as well as in modulating proliferative and hypertrophic growth in fetal and adult organs. Exogenous FGF2 (also known as basic FGF) was found to be able to induce proliferation of chick embryonic and fetal cardiac myocytes in vivo and is also important for vascular development. The aim of this study was to assess the effect of FGF2 signaling on growth of chick embryonic ventricular wall and its vascularization. Methods: In the first set of experiments, left ventricular wall of E7 chick embryos was injected with either GFP-expressing replication-deficient adenovirus alone or in combination with adenoviral vector encoding human FGF-2 gene. In the second set of experiments, FGF signaling was blocked in E8 chick embryos using FGF receptor tyrosine kinase inhibitor SU 5402. Hearts were sampled at ED9 for both protocols. In the third set of experiments we tested whether FGF2 signaling is involved in transmission of mechanical stretch to myocyte growth in vivo using an established pressure overload model. Results: (1) Morphological examination of adenovirus-injected hearts revealed no difference in normal myocardial architecture, but increased levels of myocyte proliferation in hearts injected with FGF-2 adenovirus. There was no difference in capillary density or coronary artery anomalies. (2) Blocking of FGF signaling with SU 5402 led to hemorrhages in the areas of developing vasculature in epicardium. However, rates of myocyte proliferation were unchanged. (3) In pressure-overloaded hearts proliferation was increased significantly at the 48h sampling interval. Neither Western blot, nor immunohistochemistry performed on paraffin sections revealed any changes in the amount of myocardial FGF2. However, ELISA showed a significant increase of FGF2 in the serum. Increased amount of FGF2 mRNA in heart extracts was confirmed by RT PCR. We conclude that up-regulation of FGF2 signaling has a positive effect on growth of the embryonic heart, while its inhibition impacts mainly vasculogenesis, pointing to partial functional redundancy in paracrine control of cell proliferation in the developing heart. FGF2 synthesis is induced in embryonic ventricular cardiomyocytes in response to increased stretch due to pressure overload. However, increased stretch causes its release into serum, causing it to act in endocrine, rather then the usual paracrine manner.

Cells

Our dream of defeating the processes of aging has occupied the curious and has challenged scienti... more Our dream of defeating the processes of aging has occupied the curious and has challenged scientists globally for hundreds of years. The history is long, and sadly, the solution is still elusive. Our endeavors to reverse the magnitude of damaging cellular and molecular alterations resulted in only a few, yet significant advancements. Furthermore, as our lifespan increases, physicians are facing more mind-bending questions in their routine practice than ever before. Although the ultimate goal is to successfully treat the body as a whole, steps towards regenerating individual organs are even considered significant. As our initial approach to enhance the endogenous restorative capacity by delivering exogenous progenitor cells appears limited, we propose, utilizing small molecules critical during embryonic development may prove to be a powerful tool to increase regeneration and to reverse the processes associated with aging. In this review, we introduce Thymosin beta-4, a 43aa secreted ...

Journal of molecular and cellular cardiology, Jan 5, 2015

Repairing defective cardiac cells is important towards improving heart function. Due to the frequ... more Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered Thymosin β4 (TB4), a 43 amino-acid secreted actin sequestering peptide, is beneficial for myocardial cell survival and coronary re-growth after infarction in adult mammals. Considering the regenerative potential of full-length TB4 in the heart, and that minimal structural variations alter TB4's influence on actin assembly and cell movement, we investigated how various TB4 domains affect cardiac cell behavior and post-ischemic mammalian heart function. We synthesized 17 domain combinations of full-length TB4 and analyzed their impact on embryonic cardiac cells in vitro, and after cardiac infarction in vivo. We discovered the domains of TB4 affect cardiac cell behavior distinctly. We revealed TB4 specific C-terminal tetrapept...

Nature Communications, 2014

Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (h... more Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T4 (T4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

Trends in Cardiovascular Medicine, 2008

Myocardial damage is frequently occurring upon a prolonged period of ischemia, although subsequen... more Myocardial damage is frequently occurring upon a prolonged period of ischemia, although subsequent reperfusion as standard therapy is established. Among the pleiotropic causes of ischema-reperfusion injury, loss of cardiomyocytes, microcirculatory disturbances, and postischemic inflammation have been frequently observed. Current clinical cell therapy after acute myocardial mostly aims at neovascularization and enhancement of tissue repair, whereas acute cardioprotection after ischemia and reperfusion has rarely been studied. Recently, embryonic endothelial progenitor cells (eEPCs) have been found to provide cardioprotection against acute ischemia-reperfusion injury (24 hours) in a preclinical pig model. The paracrine effect of eEPCs was mimicked by regional application of a single, highly expressed protein, Thymosin beta4. This review focuses on underlying mechanisms of acute cardioprotection provided by eEPCs and, in particular, Thymosin beta4.

Nature, 2004

Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote c... more Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote cardiac repair through the use of stem cells hold promise but typically involve isolation and introduction of progenitor cells. Here, we show that the G-actin sequestering peptide thymosin b4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin b4. We found that thymosin b4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (also known as protein kinase B). After coronary artery ligation in mice, thymosin b4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival and improved cardiac function. These findings suggest that thymosin b4 promotes cardiomyocyte migration, survival and repair and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.

Journal of Molecular and Cellular Cardiology, 2009

Hypoxic heart disease is a predominant cause of disability and death worldwide. Since adult mamma... more Hypoxic heart disease is a predominant cause of disability and death worldwide. Since adult mammalian hearts are incapable of regeneration after hypoxia, attempts to modify this deficiency are critical. As demonstrated in zebrafish, recall of the embryonic developmental program may be the key to success. Because thymosin β4 (TB4) is beneficial for myocardial cell survival and essential for coronary development in embryos, we hypothesized that it reactivates the embryonic developmental program and initiates epicardial progenitor mobilization in adult mammals. We found that TB4 stimulates capillary-like tube formation of adult coronary endothelial cells and increases embryonic endothelial cell migration and proliferation in vitro. The increase of blood vessel/ epicardial substance (Bves) expressing cells accompanied by elevated VEGF, Flk-1, TGF-β, FGFR-2, FGFR-4, FGF-17 and β-Catenin expression and increase of Tbx-18 and Wt-1 positive myocardial progenitors suggested organ-wide recall of the embryonic program in the adult epicardium. TB4 also positively regulated the expression and phosphorylation of myristoylated

Circulation, 2008

Background— Prolonged myocardial ischemia results in cardiomyocyte loss despite successful revasc... more Background— Prolonged myocardial ischemia results in cardiomyocyte loss despite successful revascularization. We have reported that retrograde application of embryonic endothelial progenitor cells (eEPCs) provides rapid paracrine protection against ischemia-reperfusion injury. Here, we investigated the role of thymosin β4 (Tβ4) as a mediator of eEPC-mediated cardioprotection. Methods and Results— In vitro, neonatal rat cardiomyocytes were subjected to hypoxia-reoxygenation in the absence or presence of eEPCs with or without Tβ4 short hairpin RNA (shRNA) transfection. In vivo, pigs (n=9 per group) underwent percutaneous left anterior descending artery occlusion for 60 minutes on day 1. After 55 minutes of ischemia, control eEPCs (5×10 6 cells) or cells transfected with Tβ4 shRNA when indicated or 15 mg Tβ4 alone were retroinfused into the anterior interventricular vein. Segmental endocardial shortening in the infarct zone at 150-bpm atrial pacing, infarct size (triphenyl tetrazolium ...

Annals of the New York Academy of Sciences, 2007

Heart disease is a leading cause of death in newborns and in adults. Efforts to promote cardiac r... more Heart disease is a leading cause of death in newborns and in adults. Efforts to promote cardiac repair by introduction or recruitment of exogenous stem cells hold promise but typically involve isolation and introduction of autologous or donor progenitor cells. We have found that the G-actin-sequestering peptide thymosin ␤4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin ␤4. We found that thymosin ␤4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt/PKB, which was necessary for thymosin ␤4's effects on cardiomyocytes. After coronary artery ligation in mice, thymosin ␤4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. These findings suggest that thymosin ␤4 promotes cardiomyocyte and endothelial migration, survival, and repair and may be a novel therapeutic target in the setting of acute myocardial damage.

Annals of the New York Academy of Sciences, 2010

Acute myocardial infarction is still one of the leading causes of death in the industrial nations... more Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin β4 shRNA was performed. Thymosin ß4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin ß4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin ß4 dependent manner.