Biomedical subjects

Ursula Müller-Werdan

Publications and source records attributed to Ursula Müller-Werdan.

At least 19 recordsLinked to original sources

PubMed2006

Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility.

OBJECTIVE: In chronic heart failure (CHF) the myocardial expression of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), which is thought to contribute to myocardial remodeling, was found to be increased. However, it is unknown whether the E3-ubiquitin ligases MAFbx and Murf-1 are involved in this remodeling process and whether their expression is regulated by TNF-alpha. METHODS: Rats underwent ligation of the left coronary artery to induce CHF or were sham-operated. The expression of MAFbx/Murf-1 and troponin I was analyzed by RT-PCR and Western blotting in the non-infarcted area of the left ventricle. In cell culture experiments the potency of TNF-alpha to stimulate Murf-1/MAFbx expression, the intracellular signaling pathway, and the involvement of the E3-ligases for the impairment of contractility were assessed. RESULTS: In CHF the myocardial expression of TNF-alpha was elevated 3.1-fold as compared to control. This was associated with a 4.5-fold and 2.7-fold increase in MAFbx and Murf-1 expression, respectively. A positive correlation between TNF-alpha and the expression of MAFbx or Murf-1 was evident. In neonatal rat cardiomyocytes, TNF-alpha induced the expression of MAFbx through p38MAPK-dependent pathways, whereas the induction of Murf-1 required the activation of the p42/44 MAPK pathway. Exposure of cardiomyocytes to TNF-alpha resulted in troponin I ubiquitinylation, subsequent degradation, and a decline in contractility. This was completely abrogated by siRNAs against Murf-1/MAFbx. CONCLUSION: TNF-alpha, which is increasingly expressed in CHF, induces troponin I degradation through a MAFbx/Murf-1-dependent pathway. This was associated with an impairment of contractility and might be one mechanism involved in the adverse remodeling process in CHF.

Animals↗

PubMed2006

Making omelets without breaking eggs: E2F-mediated induction of cardiomyoycte cell proliferation without stimulation of apoptosis.

The fundamental role of E2F transcription factors in the regulation of proliferation is well established. According to a widely accepted model, E2F1, E2F2, and E2F3 are classified as "activating" E2Fs since they induce proliferation of quiescent cells whereas E2F4 and E2F5 do not have the power to incite cell cycle progression but are related to differentiation processes and were therefore considered to be "repressive". In addition, it has been postulated that "activating" E2Fs induce apoptosis in a wide variety of cell types depending on their expression level. However, we demonstrated recently that this 'threshold model' does not hold true for cardiomyocytes. In a series of experiments in which we overexpressed individual E2Fs we found that directed expression of E2F2, unlike E2F1, E2F3 and E2F5, did not induce apoptosis but even suppressed expression of several pro-apoptotic genes in primary cardiomyocytes. Furthermore, we established that not only E2F1, E2F2, and E2F3 but also E2F4 was able to induce S-phase entry of primary cardiomyocytes. Our results suggest that it is possible to utilize the proliferation-inducing properties of the E2Fs in cardiomyocytes without activation of potentially harmful pro-apoptotic traits. This finding might open a new access to stimulate regeneration in postmitotic tissues such as the heart.

Animals↗

PubMed2006

Nitric oxide synthase is up-regulated in muscle fibers in muscular dystrophy.

Nitric oxide (NO) mediates fundamental physiological actions on skeletal muscle. The neuronal NO synthase isoform (NOS1) was reported to be located exclusively in the sarcolemma. Its loss from the sarcolemma was associated with development of Duchenne muscular dystrophy (DMD). However, new studies evidence that all three NOS isoforms-NOS1, NOS2, and NOS3-are co-expressed in the sarcoplasm both in normal and in DMD skeletal muscles. To address this controversy, we assayed NOS expression in DMD myofibers in situ cytophotometrically and found NOS expression in DMD myofibers up-regulated. These results support the hypothesis that NO deficiency with consequent muscle degeneration in DMD results from NO scavenging by superoxides rather than from reduced NOS expression.

Biopsy↗

PubMed2006

Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome.

OBJECTIVE: The multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, such as sepsis, pneumonia or cardiogenic shock. Even today, mortality is high. Statin therapy is associated with reduction of inflammation and subsequent rates of severe sepsis and ICU admission of patients admitted to hospital with presumed or documented acute bacterial infection. Our study aimed to characterize a potential survival benefit by statin therapy in MODS patients. DESIGN: Retrospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Forty score-defined MODS patients under statin treatment and 80 age- and sex-matched score-defined MODS patients without statin treatment. Inclusion criterion was an APACHE II score > or = 20 at admission to ICU. INTERVENTIONS: Assessment of statin treatment and calculation of disease severity by scoring. The patients were followed up for 28-day mortality as well as for hospital mortality. MEASUREMENTS AND RESULTS: The MODS severity was equally pronounced in both groups. There were 42/80 deaths in the group without statin treatment and 13/40 deaths in the statin group (28-day mortality 53% vs. 33%, p = 0.03). Cox proportional hazard analysis revealed a hazard ratio of 0.53 (95% CI 0.29-0.99, p = 0.04). Hospital mortality was calculated at 72% (non-statin group) vs. 35% (statin group; chi-square = 15.6, p < 0.0001). The overall hospital mortality was 60%. CONCLUSIONS: Patients under statin treatment developing MODS might have a better outcome than patients without statin therapy, probably by reduction of inflammatory responses and increase of vagal activity in MODS.

Atorvastatin↗

PubMed2006

Proteome analysis of myocardial tissue following ischemia and reperfusion--effects of complement inhibition.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic mediators, release of cytokines, leukocyte accumulation, and subsequent severe tissue injury. In this regard, activation of transcription factors (i.e., NFkappaB) and de novo protein synthesis or inflammatory protein degradation seems to play an important role. In the present study, we analyzed the cardiac protein expression following myocardial ischemia (60 min) and reperfusion (180 min) in a rabbit model utilizing two-dimensional electrophoresis and nanoHPLC/ESI-MS/MS for biochemical protein identification. To achieve cardioprotective effects, we used a novel highly selective small molecule C1s inhibitor administered 5 min prior to reperfusion. The reduction of myocardial injury was observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (65.2+/-3 vs. 38.5+/-3 U/g protein after 3 h of reperfusion, P<0.05). With proteome analysis we were able to detect 509+/-21 protein spots on the gels of the 3 groups. A pattern of 480 spots with identical positions was found on every gel of myocardial tissue of sham animals, vehicle and C1s-INH-248-treated animals. We analyzed 11 spots, which were identified by mass spectrometry: Superoxide dismutase, alpha-crystallin-chain-B, mitochondrial stress protein, Mn SOD, ATP synthase A chain heart isoform, creatine kinase, and troponin T. All of these proteins were significantly decreased in the vehicle group when we compared to sham-treated animals. Treatment with C1s-INH-248 preserved levels of these proteins. Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex archives cardio-protection by altering and preserving different anti-inflammatory and cytoprotective cascades.

Amino Acid Sequence↗

PubMed2006

Nitric oxide synthase in muscular dystrophies: a re-evaluation.

Duchenne and Becker muscular dystrophies (DMD and BMD) are associated with decreased total nitric oxide (NO). However, mechanisms leading to NO deficiency with consequent muscle-cell degeneration remain unknown. To address this issue, we examined skeletal muscles of DMD and BMD patients for co-expression of NO synthase (NOS) with nitrotyrosine and transcription factor CREB, as well as with enzymes engaged in NO signaling. Employing immunocytochemical labeling, Western blotting and RT-PCR, we found that, in contrast to the most commonly accepted view, neuronal NOS was not restricted to the sarcolemma and that muscles of DMD and BMD patients retained all three NOS isoforms with an up-regulation of the inducible NOS isoform, CREB and nitrotyrosine. We suggest that enhanced nitrotyrosine immunostaining in muscle fibers as well as in the vasculature of DMD and BMD specimens reflects massive oxidative stress, resulting in withdrawal of NO from its regular physiological course via the scavenging actions of superoxides.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Analysis of complex physiological systems by information flow: a time scale-specific complexity assessment.

In the last two decades conventional linear methods for biosignal analysis have been substantially extended by non-stationary, non-linear, and complexity approaches. So far, complexity is usually assessed with regard to one single time scale, disregarding complex physiology organised on different time scales. This shortcoming was overcome and medically evaluated by information flow functions developed in our research group in collaboration with several theoretical, experimental, and clinical partners. In the present work, the information flow is introduced and typical information flow characteristics are demonstrated. The prognostic value of autonomic information flow (AIF), which reflects communication in the cardiovascular system, was shown in patients with multiple organ dysfunction syndrome and in patients with heart failure. Gait information flow (GIF), which reflects communication in the motor control system during walking, was introduced to discriminate between controls and elderly patients suffering from low back pain. The applications presented for the theoretically based approach of information flow confirm its value for the identification of complex physiological systems. The medical relevance has to be confirmed by comprehensive clinical studies. These information flow measures substantially extend the established linear and complexity measures in biosignal analysis.

Adult↗

PubMed2006

Attenuated autonomic function in multiple organ dysfunction syndrome across three age groups.

Multiple organ dysfunction syndrome (MODS) is the failure of several organs after a trigger event. The mortality is high, at up to 70%. We hypothesize that autonomic dysfunction may substantially contribute to the development of MODS and speculate that there is an age dependence of autonomic dysfunction in MODS. A total of 90 consecutively admitted MODS patients were assigned to this study. Three variables of autonomic function were analyzed: heart rate variability (HRV), baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS). The patient cohort was divided into three age groups. The main finding was that BRS, CRS and almost all indices of HRV were attenuated in comparison to normal range data and there was no age dependence for HRV indices or CRS, but there was for BRS. In conclusion, autonomic function in MODS is attenuated. The influence of MODS on autonomic function overwhelms the age dependence of autonomic function observed in healthy subjects.

Aging↗

PubMed2006

Genetic impact of TNF-beta on risk factors for coronary atherosclerosis.

BACKGROUND: Inflammatory processes are considered to play an important role in the development of coronary atherosclerosis. The proinflammatory cytokine, tumor necrosis factor beta (TNF-beta), is thought to contribute to the pathogenesis of atherosclerosis. STUDY DESIGN: In this clinical study, the influence of genetic variants of TNF-beta (c.7G>A, IVS1+90G>A, C13R, T60N) on major coronary risk factors, including gender, smoking, history of cardiovascular diseases, biochemical data (inflammatory markers, factors of lipid metabolism, coagulation/fibrinolysis balance), and angiographically-proven coronary state, was investigated in 176 European Caucasian probands (130 males, mean age: 51.9 +/- 8.9 y). RESULTS: The most frequent combinations of the polymorphisms investigated were significantly associated with four of the coronary risk factors evaluated: hypertension, body mass index, the common inflammatory marker TNF-alpha (mRNA expression), and fibrinogen (p < 0.05). However, on testing the impact of the genetic background on the incidence of coronary stenosis in this sample of European Caucasians, no significant influence of these polymorphisms (stepwise binary logistic regression analysis) could be proven. These findings emphasise a distinct influence of TNF-beta polymorphisms on important modulators of the development of coronary atherosclerosis, but exclude its genetic background, investigated in this study as an independent coronary risk factor.

Adult↗

PubMed2005

Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients.

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, like cardiogenic shock or decompensated heart failure. Mortality is high, up to 70%. Autonomic dysfunction (AD) may substantially contribute to the development of MODS. In cardiology, it has recently been shown that nonlinear parameters could predict mortality. Our study aimed at 1. characterising the complex characteristics of AD of critically ill MODS patients by the nonlinear parameters of autonomic information flow (AIF), 2. comparing AIF with autonomic function of healthy controls, and 3. characterising the accuracy of this parameter in predicting mortality in MODS. METHODS: We enrolled 43 score-defined MODS patients who were consecutively admitted to a twelve-bed medical intensive care unit in a university centre into this prospective outcome study. Additionally, we assigned 50 healthy controls to the study. AIF was assessed as a complexity function of AD using 24-h ECG. Measures of AIF were introduced according to the standard HRV concept. The patients were followed up for 28-day mortality. RESULTS: MODS causes a disorganisation of short term AIF in favour of an enhanced (rigid) long term AIF. Concerning prognosis increased short term AIF was associated with survival. Short term AIF discriminated between MODS survivors and non-survivors at the level of APACHE II score. CONCLUSIONS: This is the first study providing evidence that complex AD of MODS patients is specifically assessed by AIF time scales and that AIF has significant prognostic impact.

Adult↗

PubMed2005

The human FGF2 level is influenced by genetic predisposition.

BACKGROUND: The fibroblast growth factor 2 (FGF2) is involved in various processes possibly leading to the development of complex diseases such as atherosclerosis. In recent studies, its cardioprotective properties, due to its ability to stimulate the proliferation of collateral vessels, could be shown. STUDY DESIGN: In this clinical study, the relation between clinical risk markers, a genomic variant of FGF2, namely the c.223C>T polymorphism, and the in vivo FGF2 expression was evaluated. Therefore, 198 clinically well-characterized probands, all of Caucasian origin, were included. The FGF2 mRNA level was determined in monocytes by competitive RT-PCR, whereas the plasma level of circulating FGF2 protein was analysed by ELISA. By considering the angiographically proven stenotic state of the patient, a significant increase in FGF2 mRNA, but not in protein level, could be shown for patients with significant stenosis. Apart from this, no influence on FGF2 expression was found in the case of all of the clinical and biochemical markers investigated. However, in the case of the c.223C>T polymorphism, a significant increase in the individual FGF2 mRNA and protein level in CC-carriers was shown. In multivariate analysis, this relation was independent of all other risk markers investigated. CONCLUSIONS: Our results suggest that an increase in FGF2 mRNA expression, related to coronary atherosclerosis, may be necessary for the maintenance of the individual FGF2 plasma level. Since the individual FGF2 mRNA and protein level are, to a large extent, triggered off by genetic background, the FGF2 expression cannot be referred to as an independent clinical marker for CAD.

Coronary Artery Disease↗

PubMed2005

Divergent siblings: E2F2 and E2F4 but not E2F1 and E2F3 induce DNA synthesis in cardiomyocytes without activation of apoptosis.

Proliferation of mammalian cardiomyocytes ceases around birth when a transition from hyperplastic to hypertrophic myocardial growth occurs. Previous studies demonstrated that directed expression of the transcription factor E2F1 induces S-phase entry in cardiomyocytes along with stimulation of programmed cell death. Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression. Although both E2F2 and E2F4 induced S-phase entry only directed expression of E2F2 resulted in mitotic cell division of cardiomyocytes. Expression of E2F5 or a control LacZ-Adenovirus had no effects on cell cycle progression. Quantitative real time PCR revealed that E2F1, E2F2, E2F3, and E2F4 alleviate G0 arrest by induction of cyclinA and E cyclins. Furthermore, directed expression of E2F1, E2F3, and E2F5 led to a transcriptional activation of several proapoptotic genes, which were mitigated by E2F2 and E2F4. Our finding that expression of E2F2 induces cell division of cardiomyocytes along with a suppression of proapoptotic genes might open a new access to improve the regenerative capacity of cardiomyocytes.

Adenoviridae↗

PubMed2005

Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups.

OBJECTIVE: Multiple organ dysfunction syndrome (MODS) is the sequential failure of several organ systems after a trigger event, like sepsis or cardiogenic shock. Mortality rate is high, up to 70%. Autonomic dysfunction may substantially contribute to the development of MODS. Our study aimed to characterize a) the spectrum of autonomic dysfunction of critically ill MODS patients; b) whether autonomic dysfunction is different in patients receiving sedation, mechanical ventilation, or catecholamines; c) the age dependency of autonomic dysfunction in MODS; and d) whether autonomic dysfunction predicts mortality in MODS. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Ninety consecutively admitted score-defined MODS patients. INTERVENTIONS: Assessment of heart rate variability, baroreflex sensitivity, and chemoreflex sensitivity as markers of autonomic dysfunction. The patients were followed for 28-day mortality. MEASUREMENTS AND MAIN RESULTS: Baroreflex sensitivity, chemoreflex sensitivity, and almost all indexes of heart rate variability were attenuated in comparison to normal range data. There was no association between the assessed heart rate variability variables, baroreflex sensitivity or chemoreflex sensitivity, and the presence of sedation or catecholamine therapy. Except for frequency-domain variables, pNN50 (percentage of differences of successive RR intervals differing >50 msecs) and rMSSD (root mean square of successive difference of N-N intervals), none of the measured variables were related to the presence of mechanical ventilation. Age dependency was detected for baroreflex sensitivity but not for heart rate variability indexes or chemoreflex sensitivity (across ages 24-96 yrs). lnVLF predicted 28-day mortality best in the entire cohort of patients and in a subgroup of patients with cardiogenic-triggered MODS. CONCLUSIONS: Autonomic function of MODS patients is blunted, and this attenuation has prognostic implications. The extensive influence of MODS on autonomic function overwhelms and masks the well-known age dependency of autonomic function seen in healthy persons.

Adult↗

PubMed2005

Optimal maximum tracking rate of dual-chamber pacemakers required by children and young adults for a maximal cardiorespiratory performance.

INTRODUCTION: Children and young adults require a higher maximum tracking rate (MTR) for physical activity. The objective of the present study was to observe whether higher MTR of 170 or 190 beats per minute (bpm) have a positive impact on the maximal cardiorespiratory capacity of children and young adults in comparison with a lower MTR of 140 bpm. METHODS: Fifteen patients with atrioventricular block and normal sinus-node chronotropic function (age 7-24 years) with DDD- (14) or VDD-pacemakers (PM) (1) were enrolled. First, the MTR was adjusted to 140 bpm for 6 weeks and elevated in a second step to 170 or 190 bpm. At the end of each period two cardiopulmonary exercise tests, a 24-hour ECG and a PM test were performed. RESULTS: All patients increased their maximal heart rate (139.0 +/- 1.0 vs 177.0 +/- 10.0 bpm, P < 0.001), peak cardiorespiratory capacity (2.4 +/- 0.6 vs 2.8 +/- 0.7 W/kg, P < 0.001), peak oxygen uptake (28.3 +/- 7.0 vs 35.7 +/- 9.5 mL/kg/min, P < 0.005), and oxygen uptake (23.7 +/- 7.4 vs 29.3 +/- 8.4 mL/kg/min, P < 0.02) at the anaerobic threshold. There were no evident heart rhythm disturbances with elevated MTR. Patients with a Wenckebach behavior of the PM had an attenuated increase of maximal cardiorespiratory performance. CONCLUSION: Children and young adults with DDD-/VDD-PM benefit from an elevated MTR by an increased cardiorespiratory capacity, without having more heart rhythm disturbances. A Wenckebach behavior of the PM should be avoided.

Adolescent↗

PubMed2004

Impaired chemoreflex sensitivity in adult patients with multiple organ dysfunction syndrome--the potential role of disease severity.

OBJECTIVE: The cardiac chemoreflex sensitivity is a powerful predictor of autonomic dysfunction in chronic heart failure and after myocardial infarction. The objective of the present study was to characterize cardiac chemoreflex sensitivity in patients with multiple organ dysfunction syndrome (MODS). We also aimed to elucidate the effect of the severity of MODS on the assessment of cardiac chemoreflex sensitivity. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Forty consecutively admitted patients with MODS during a 7-month period. Patients with MODS were identified by an APACHE II score of 20 or more. Sepsis was defined as a Sepsis Score, according to Elebute and Stoner, of 12 or more. INTERVENTIONS: The cardiac chemoreflex sensitivity was assessed using the regression of heart interval (ms) versus arterial oxygen pressure (mmHg). MEASUREMENTS AND RESULTS: First, we established a new method to assess cardiac chemoreflex sensitivity and applied it to healthy controls and patients. Second, we found that cardiac chemoreflex sensitivity correlated with the severity of MODS as calculated by the APACHE II score ( r(2)=0.34, p=0.001). This relation was best fitted by a model including minimum heart rate and standard bicarbonate in 24 h ( r(2)=0.5, p<0.001) and Glasgow Coma Scale ( r(2)=0.5, p=0.005). Age, however, did not significantly contribute ( r(2)=0.001, p=0.8). CONCLUSIONS: The calculation of cardiac chemoreflex sensitivity enabled us to quantify an important component of the cardiorespiratory interactions in patients with MODS. Severity of illness was a more pronounced determinant of impaired cardiac chemoreflex sensitivity than age. The quantification of the cardiorespiratory interactions by measuring the cardiac chemoreflex sensitivity has potential to identify a subgroup of patients with worse prognosis.

APACHE↗

PubMed2003

Role of LDL receptor-related protein (LRP) in coronary atherosclerosis.

The development and progression of coronary atherosclerosis is influenced by a variety of genetic and environmental factors. Among the genetic factors, the cell surface receptor LRP/A2MR (LDL receptor-related protein/alpha2-macroglobulin receptor) was shown to be involved in a variety of biological processes leading to atherosclerotic plaque formation. That is why the individual expression of this receptor may, therefore, be considered as an evident predictor for coronary atherosclerosis. In this clinical ex vivo study the expression was measured by competitive RT-PCR and macroarray analysis in native monocytes. Both methods were first tested in an in vitro model using different human cells and cell lines (fibroblasts: chorion, skin; endothelial cells from umbilical cord vein; monocyte cell line: Mono-Mac-6): after stimulation with an LRP/A2MR ligand, leptin, the anticipated direct effect of this ligand, namely an increase in both receptor mRNA and protein expression, was confirmed. In disease-related ex vivo studies the mRNA and protein-expression of LRP/A2MR was investigated in 36 male patients suffering from myocardial infarction. In comparison to the control group (36 healthy male blood donors), a significant up-regulation of mRNA was detected in the myocardial infarction patient group (control: 122.3 ag/cell versus patients: 223 ag/cell; P<0.001). Investigating the LRP/A2MR protein expression a significant down-regulation of protein expression was determined in the patient group (control: 6 pg/cell versus patients: 1.6 pg/cell; P<0.001). The ratio of LRP/A2MR mRNA and protein expression is obviously an evident marker for coronary atherosclerosis, recommendable for the assessment of the individual coronary risk profile.

Blood Donors↗

PubMed2002

The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis--novel genomic variants and functional consequences.

The LDL receptor-related protein/alpha 2-macroglobulin receptor (LRP1/A2MR) is a multifunctional cell-surface glycoprotein that endocytoses several structurally and functionally distinct ligands. In clinical studies different genomic variants of the LRP1/A2MR and its role in the development of degenerative diseases like atherosclerosis or Alzheimer's disease were studied. We screened for novel genomic variants of LRP1/A2MR and investigated the importance of these variants in 214 coronary patients suffering from myocardial infarction as well as in 224 healthy controls. We detected a novel C>G polymorphism at position -25 in the functionally important promoter region of LRP1/A2MR. This polymorphism (c.1-25C>G) leads to the creation of a new GC-box, recognized by the constitutively expressed SP 1 transcription factor. Investigating the LRP1/A2MR gene expression with respect to this polymorphism, carriers of the mutant G-allele were found to have a higher mRNA expression level. A novel polymorphism in exon 22 (c.4012C>T), and two novel polymorphisms in intron 24 (IVS24+123C>A and IVS24+690G>A) associated with a previously described polymorphism in exon 61 (c.10249G>A), were related to the development of myocardial infarction. Two novel rare genetic variants of exon 88 (c.13933C>T) and intron 88 (IVS88+15G>A) were identified in four patients with severe coronary symptoms. However, the LRP1/A2MR gene expression was found to be independent of all identified novel genomic variants as well as other previously described changes (A217V, A775P, D2080N, D2632E, G4379S) except the promoter polymorphism.

Adult↗

PubMed2002

The ageing heart: influence of cellular and tissue ageing on total content and distribution of the variants of elongation factor-2.

The involvement of elongation factor-2 (EEF-2), a key-protein of peptide-chain elongation, in the slowing down of protein synthesis during cardiac ageing was addressed. EEF-2 was measured in rat heart extracts and isolated rat cardiomyocytes (CM) from newborn and adult rats using sodium-dodecylsulphate polyacrylamide gel electrophoresis after specific labeling with [32P]ADP-ribosylation or immunoblot. The age-dependent proportional content of several eucaryotic elongation factor-2 (eEF-2) subtypes in rat CM and rat heart extracts was compared using one-dimensional isoelectric focusing. EEF-2 was considerably reduced in the hearts of adult compared to neonatal rats (P<0.01). EEF-2 was also significantly decreased in isolated CM from adult versus newborn rats and during prolonged cultivation of neonatal CM. Cellular ageing was combined with reduced protein synthesis. During adolescence the eEF-2 variants shifted to acidic subtypes. Young adult and old rats revealed similar amounts and subtype distribution of cardiac eEF-2. Only the more acidic eEF-2 variants appeared to contain phosphorylated eEF-2. We concluded that total cardiac eEF-2 and its subtype pattern might play an important role in developmental and age-related proteomic changes.

Adenosine Diphosphate↗