Coordinators:
Emil MONOS M.D., Ph.D., D.Sc.
Zoltán BENYÓ M.D., Ph.D., D.Sc.
Institute of Human Physiology and Clinical Experimental Research
Basic Medical Science Center 37–47 Tûzoltó st, Budapest H–1094
Tel.: +36 1 210 6038, Tel./fax: +36 1 334 3162 E-mail: monos,[email protected]
Program overview
The program consists of 12 research sub-programs with several special projects completed with appropriate theoretical courses for postgraduate students. Different aspects of normal and disturbed regulatory processes of the cardiovascular system are in the focus. Each Ph.D. student is working on his/her own individual research project under the guidance of a qualified scientific advisor. Successful completion of the Program including publications in recognized international journals provides an opportunity to summarize the results in a Ph.D. thesis.
Titles of research projects Supervisors
Pathophysiology of the cerebral circulation Zoltán Benyó Cardiovascular adaptational mechanisms in the whole body,
as well as the myocardium and the brain cortex László Dézsi Role of bradykinin receptors in the circulatory adaptation under
normal and pathological conditions; interactions with other mechanisms affecting blood pressure
László Dézsi
Spatio-temporal correlation of coupled hemodynamics and
neuronal activities in the brain András Eke
Role of postmenopausal hormonal deficiencies in altering the
fractal structuring of hemodynamic fluctuations in the brain cortex András Eke Impact of cerebralsclerosis in altering the fractal structuring of
cerebrocortical hemodynamic fluctuations András Eke
Effects of blood substitutes on tissue hemodynamics and oxygenation András Eke Functional integrity of the cardiopulmonary system Ildikó Horváth Regulation of calcium homeostasis in the myocardial tissue Tamás Ivanics Alterations of the intracellular calcium homeostasis in progressive
heart failure Tamás Ivanics
Comparative evaluation of clinical and epidemiological diagnostic methods in the assessment of cardiovascular autonomic and peripheral sensory neuropathy
Péter Kempler
The mechanism of action of cell-based regenerative therapies in
myocardial infarct Levente Kiss
Investigation of vascular functions affecting the autonomous
cardio-vascular tone and reflex activity Márk Kollai
Cardiovascular autonomous neural system Márk Kollai The role of mitochondria in ischemic and degenerative diseases Zsombor Lacza Adaptation mechanisms of hemodynamic functions and network
properties of the vascular system to physiological and to pathological loading
György Nádasy
Alterations of the biomechanical properties of extremity arteries
and veins during angiogenetic processes György Nádasy, Emil Monos Alterations of biomechanical and network properties of intramural
coronary resistance arteries with aging, hypertension and in other angiogenetic processes
György Nádasy, Emil Monos Videomicroscopic analysis of ureteral movements. Pharmacological
and pathological effects György Nádasy,
Imre Romics Ischemia-induced molecular-biological changes of the blood-brain
barrier Péter Sándor
The role of the female sex hormones in the regulation of the cerebral
blood flow Péter Sándor
Role of oxidative stress in pathophysiology of cardiovascular system Csaba Szabó Study of promoting and inhibiting factors in cardiovascular aging Béla Székács Hormon-dependent cardiovascular adaptation mechanisms in
normo- and hypertension in females Szabolcs Várbíró
Ph.D. students Supervisors
András Iring ft Zoltán Benyó
Péter Kemecsei ft Tamás Ivanics
Tímea Martos ft Péter Kempler
Katalin Módis ft Csaba Szabó
Nóra Németh ft Zsolt Rónai
Tamás Németh ft (a) Zoltán Benyó
Ágoston Pasztuhov pt Péter Tóth
Alexandra Pintér ft Márk Kollai
a, absolutorium; ft, full-time; pt, part-time; i, individual; na, not affiliated
Abstracts of Ph.D. theses successfully defended in 2009 and 2010
RITA BENKÔ (2009)
The role of poly(ADP-ribose) polymerase-1 in the pathogenesis of chronic cardiovascular diseases
Supervisor: Csaba Szabó Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension, and aging. Oxidant-induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP). Oxidant-mediated activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) plays a role in the development of endothe-lial dysfunction and the pathogenesis of various cardiovascular diseases, including diabetes, reperfusion injury, circulatory shock, and aging. Earlier studies found increased amounts of poly(ADP) ribosylated proteins in diabetic heart, vessels in both human and animal samples, and also in kidneys of Leprdb/db(BKsJ) mice, suggesting increased PARP activity. The aim of the present studies were to investigate (1) the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar’s new Aria pressure-volume conductance system and isolated aortic
Ph.D. candidates Supervisors
Zsolt Hermányi pt Péter Kepler
Gábor Lenzsér ft Péter Sándor
Miriam Leszl-Ishiguro ft Zoltán Benyó
Petra Ôrsy ft Zoltán Benyó
Eszter Pankotai ft Zsombor Lacza
István Portörô ft András Eke
Éva Ruisanchez ft (a) Zoltán Benyó
Emese Szelke na Péter Sándor
Levente Sára pt Szabolcs Várbíró
Ádám Domonkos Tárnoki pt Viktor Bérczi
Dávid László Tárnoki pt Viktor Bérczi
Bernadett Trencsényiné Balázs ft Ákos Zsembery
Gabriella Vácz ft Zsombor Lacza
Miklós Weszl ft Zsombor Lacza
Ph.D. graduates Supervisors
Rita Benkô ft Csaba Szabó
Eszter Mária Horváth ft Csaba Szabó
Ildikó Istenes ft Péter Kempler
Levente Kiss ft Csaba Szabó
Zsuzsanna Putz ft Péter Kempler
rings; (2) the effects of INO-1001 on the development of diabetic endothelial dysfunction of Leprdb/db(BKsJ) mice, an experimental model of type 2 diabetes; (3) whether the acti-vation of PARP contributes to the development of endothelial dysfunction in the apolipo-protein E (ApoE) deficient mice; (4) as peroxynitrite is a potent cytotoxic oxidant pro-duced from nitric oxide (NO) and superoxide anion during conditions of oxidative stress, and it leads to PARP activation, the purpose of our next study was to determine the effects of a peroxynitrite decomposition catalyst (WW85) on the endothelial dysfunction and neointima formation in a rat model of carotid artery injury; (5) whether activation of the nuclear enzyme PARP contributes to the development of angiotensin II-induced endothelial dysfunction. In these studies, certain links were investigated between ageing, diabetic complications, atherosclerosis, hypertension on the level of reactive species for-mation and PARP activation using animal models. We observed that pharmacological inhibition of PARP protected the cardiovascular system in these pathological states.
• Benko R, Pacher P, Vaslin A, Kollai M, Szabo C (2004) Restoration of the endothelial function in the aortic rings of apolipoprotein E deficient mice by pharmacological inhibition of the nuclear enzyme poly(ADP-ribose) polymerase. Life Sci 75: 1255–1261.
• Pacher P, Vaslin A, Benko R, Mabley JG, Liaudet L, Hasko G, Marton A, Batkai S, Kollai M, Szabo C (2004) A new, potent poly(ADP-ribose) polymerase inhibitor improves cardiac and vascular dysfunction associated with advanced aging. J Pharmacol Exp Ther 311:
485–491.
• Szabo C, Biser A, Benko R, Bottinger E, Susztak K (2006) Poly(ADP-ribose) polymerase inhibitors ameliorate nephropathy of type 2 diabetic Leprdb/db mice. Diabetes 55: 3004–
3012.
ESZTER MÁRIA HORVÁTH (2009)
Poly (ADP-ribose) polymerase activation in circulating leukocytes
Supervisor: Csaba Szabó PARP activation significantly contributes to the pathogenesis of various conditions, such as endotoxin shock and myocardial infarction. Pharmacological inhibitors of PARP move toward clinical testing for a variety of indications including cardioprotection and malig-nant tumors. Our aim was to identify possible novel modulators of PARP, that may influence the outcome of these studies and to test weather measuring PARP activity in circulating leukocytes may serve as a sentinel test reflecting the degree of PARP activation and the efficiency of PARP inhibition.
Our results showed that in LPS treated female mice/rats LPS-induced TNF-α production and endothelial dysfunction were markedly attenuated, and in contrast to male mice/rats, pharmacological inhibition of PARP failed to provide further protection. The gender dif-ference in TNF-α production is partially diminished by ovariectomy. In circulating leuko-cytes, the PARP inhibitor PJ34 only inhibited LPS-induced PARP activation in males. Our observations demonstrate that there is an interrelated regulation of the endotoxin-induced inflammatory and vascular responses by gender and PARP.
We demonstrated that insulin therapy in a rat model of endotoxemia blocks PARP activation and prevents inflammatory mediator production. Insulin treatment prevented LPS-induced hyperglycemic response, blocked PARP activation in circulating leukocytes and blunted LPS-induced TNF-α response. Insulin treatment caused a slight reduction in PARP activity of mononuclear cells and HUVECs in elevated glucose conditions in vitro.
In the examined population of cardiovascular patients STEMI followed by PCI is accom-panied by increased nitrosative stress, PARP activation, and consequent AIF translocation in circulating leukocytes. These data provide evidence for PARP activation for the first time in humans suffering from myocardial infarction.
In all studies PARP activity of mononuclear cells reflected the pathological condition and the efficiency of PARP inhibition therapy.
Our observations indicate that estrogen is a novel endogenous inhibitor of PARP. Gender differences and PARP-inhibitory effect of insulin therapy has to be considered in pharma-cological development and upcoming clinical trials of PARP inhibitors. Measuring the PARP activity of circulating leukocytes may serve as potential sentinel in these studies.
• Horvath EM, Benko R, Gero D, Kiss L, Szabo C (2008) Treatment with insulin inhibits poly(ADP-ribose)polymerase activation in a rat model of endotoxemia. Life Sci 82:
205–209.
• Toth-Zsamboki E, Horvath E, Vargova K, Pankotai E, Murthy K, Zsengeller Z, Barany T, Pek T, Fekete K, Kiss RG, Preda I, Lacza Z, Gero D, Szabo C (2006) Activation of poly(ADP-ribose) polymerase by myocardial ischemia and coronary reperfusion in human circulating leukocytes. Mol Med 12: 221–228.
• Mabley JG, Horvath EM, Murthy KG, Zsengeller Z, Vaslin A, Benko R, Kollai M, Szabo C (2005) Gender differences in the endotoxin-induced inflammatory and vascular responses:
potential role of poly (ADP-ribose) polymerase activation. J Pharmacol Exp Ther 315:
812–820.
ILDIKÓ ISTENES (2009)
Relationship between hypertension, autonomic neuropathy and the cardiovascular reflextests in type 2 diabetes
Supervisor: Péter Kempler The early diagnosis of cardiovascular autonomic neuropathy is very important, since it is a serious complication of diabetes. Therefore, the correct evaluation of the five standard cardiovascular reflextests is of pivotal importance. Onehundred and twenty-five diabetic patients and onehundred and twelve healthy control subjects underwent the five stan-dard cardiovascular reflextests. According to our data, heart rate changes to deep breath-ing are affected by the patient’s age, therefore it has to be taken into consideration at the evaluation of the results in order to avoid overestimating the prevalence of parasympa-thetic autonomic dysfunction. Orthostatic hypotension, a sign of sympaparasympa-thetic dysfunc-tion, can be affected either by the initial systolic blood pressure values or the presence of parasympathetic autonomic neuropathy (through sympathetic dominance). Therefore using the measurement of orthostatic hypotension as a single test is not recommended for the diagnosis of autonomic neuropathy. Both hypertension and autonomic neuropathy are associated with an incresed risk of cardiovacular disease and death. Both are also common occurences in subjects with diabetes, but the nature of any relationship between the two is far from clear. In our cross-sectional studies we have found that diminished heart rate variability was associated with hypertension in Type 2 diabetic patients with hypertension and the association between autonomic dysfunction (based on the five stan-dard cardiovascular reflextests) and elevated blood pressure values is present even in
nor-moalbuminuric Type 2 diabetic patients without prior history of hypertension. In this lat-ter group, the prevalence of unrecognized hypertension was twice as many in patients with autonomic neuropathy compared to those with normal autonomic function. Our results support the hypothesis that relative sympathetic overactivity (due to the loss of parasympathetic counter-regulation) plays an important role in the pathogenesis of hyper-tension in Type 2 diabetes. Our results indicate that by relying simply on clinic blood pressures, hypertension is frequently unrecognized and therefore untreated. Subjects with autonomic neuropathy should therefore be screened aggressively for hypertension including with 24-hour blood pressure monitoring, if necessary and vice versa, hypertensive patients should be screened for autonomic neuropathy as well.
• Istenes I, Keresztes K, Hermányi Zs, Gyarmati G, Vargha P, Kempler P (2002) A szív-frekvencia-variabilitás beszûkülése és a hypertonia összefüggése 2-es típusú diabetes mellitusban. Diabetol Hung 10: 15–22.
• Keresztes K, Tislér A, Istenes I, Sipos É, Vargha P, Kempler P (2004) Az autonom neu-ropathia és a 24 órás ambuláns vérnyomásprofil összefüggése normalbuminuriás, 2-es típusú diabeteszes betegekben. Hypertonia és Nephrologia 8: 193–199.
• Istenes I, Keresztes K, Tündik A, Hermányi Zs, Putz Zs, Vargha P, Kertész T, Emery C, Gandhi R, Tesfaye S, Kempler P (2007) Blood pressure response to standing in the diag-nosis of autonomic neuropathy: are initial (supine) values of importance? Diabet Med 24 (3): 325–327.
LEVENTE KISS (2009)
Oxidative stress and the role of downstream pathways in cardiovascular diseases
Supervisor: Csaba Szabó Oxidative and nitrosative stress play an important role in the pathogenesis of several car-diovascular diseases, but the involved downstream pathways are still incompletely understood. Based on recent investigations, poly(ADP-ribose) polymerase and hydrogen sulfide may play an important part in these processes. The purpose of the present thesis was to further elucidate the role of poly(ADP-ribose) polymerase and hydrogen sulfide in models of cardiovascular diseases involving free radicals. In our first experiments we investigated the effects of the main oxysterol 7-ketocholesterol on the activity of endothe-lial poly(ADP-ribose) polymerase and on endothelium-dependent vasorelaxant function.
In further experiments we investigated the role of poly(ADP-ribose) polymerase in the process of cardiac remodeling and heart failure in a mouse model of heart failure induced by transverse aortic constriction. Finally, we investigated whether hydrogen sulfide has a potential to ameliorate myocardial ischemia-reperfusion injury in vivo and to explore what could be the possible underlying mechanism of action. Our experimental results indicate that: (1) although 7-ketocholesterol can activate poly(ADP-ribose) polymerase in endothelial cells, it is not sufficient on its own to cause impairment in the endothelium-dependent vascular reactivity; (2) poly(ADP-ribos)ylation plays an important role in the pathogenesis of banding-induced heart failure; (3) hydrogen sulfide may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of hydrogen sulfide or the modulation of endogenous production may be of clinical benefit
in ischemic disorders. These results stress the importance of oxidative and nitrosative stress in the investigated cardiovascular diseases and may lead to novel approaches in the therapies of atherosclerosis, ischemic heart disease and chronic heart failure.
• Xiao CY, Chen M, Zsengellér Zs, Li H, Kiss L, Kollai M, Szabó C (2005) Poly (ADP-ribose) polymerase promotes cardiac remodeling, contractile failure and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure J Pharmacol Exp Ther 312: 891–898.
• Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabó C, Kimura H, Chow CW, Lefer DJ (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 104: 15560–15565.
• Kiss L, Chen M, Gerô D, Módis K, Lacza Zs, Szabó C (2006) Effects of 7-ketocholesterol on the activity of endothelial poly (ADP-ribose) polymerase (PARP) and on endothelium-dependent relaxant function. Int J Mol Med 18: 1113–1117.
ZSUZSANNA PUTZ (2009)
Characteristics of autonomic and sensory nerve dysfunction in subjects with impaired glucose tolerance
Supervisor: Péter Kempler Autonomic and peripheral neuropathy are considered to be major complications of un-favourable prognosis in diabetes, alcoholic and non-alcoholic chronic liver disease and chronic kidney disease, which appeares in more than half of type 2 diabetic patients.
Due to the long-lasting development of type 2 diabetes, diabetes specific complications may occur even in the prediabetic state. The aim of our study was to evaluate the clinical symptoms as well as cardiovascular autonomic and peripheral sensory nerve function in patients with impaired glucose tolerance. According to our results, autonomic and sensory neuropathy are frequent complications among patients with impaired glucose tolerance.
The autonomic dysfunction which may affect both parasympathetic and sympathetic nerve system can be considerable even in case of impaired glucose tolerance. As novel finding we demonstrate the attenuation of time domain measure of heart rate variability (HRVti) in patients with impaired glucose tolerance. Several prospective studies in dia-betic patients confirmed that cardiovascular autonomic neuropathy is associated with poor prognosis. Cardiovascular autonomic neuropathy may contribute to the increased cardiovascular risk of impaired glucose tolerance. According to our results, unmyelinated small fibre damage is the characteristic feature of neuropathy in subjects with impaired glucose tolerance. Among the quantitative tests used for the assessment of sensory func-tion, the 5 Hz current perception threshold of the Neurometer and the hot detection threshold of the Medoc device seem to be appropriate for the early detection of small fibre damage. Our data suggest that these non-invasive methods may serve as an alterna-tive for the invasive punch skin biopsy used for the detection of early neuropathy among subjects with impaired glucose tolerance.
• Putz Zs, Jermendy Gy (2003) Szokatlan aetiológiájú lábsérülés diabeteses neuropathia talaján. Diabetol Hung 11: 275–277.
• Istenes I, Keresztes K, Tündik A, Hermányi Zs, Putz Zs, Vargha P, Kertész T, Emery C, Gandhi R, Tesfaye S, Kempler P (2007) Blood pressure response to standing in the diag-nosis of autonomic neuropathy: are initial (supine) values of importance. Diabet Med 24: 325–327.
• Putz Zs, Jermendy Gy (2007) Öngyógyítás okozta súlyos égési lábsérülés diabeteszes neuropathia talaján. Diabetol Hung 15: 40–42.