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1.
J Transl Med ; 17(1): 229, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324258

RESUMO

BACKGROUND: Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. METHODS: Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. RESULTS: The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. CONCLUSION: For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

2.
Front Immunol ; 10: 1240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275299

RESUMO

Galectins are potent immunomodulators that regulate maternal immune responses in pregnancy and prevent the rejection of the semi-allogeneic fetus that also occurs in miscarriages. We previously identified a gene cluster on Chromosome 19 that expresses a subfamily of galectins, including galectin-13 (Gal-13) and galectin-14 (Gal-14), which emerged in anthropoid primates. These galectins are expressed only by the placenta and induce the apoptosis of activated T lymphocytes, possibly contributing to a shifted maternal immune balance in pregnancy. The placental expression of Gal-13 and Gal-14 is decreased in preeclampsia, a life-threatening obstetrical syndrome partly attributed to maternal anti-fetal rejection. This study is aimed at revealing the effects of Gal-13 and Gal-14 on T cell functions and comparing the expression of these galectins in placentas from healthy pregnancies and miscarriages. First-trimester placentas were collected from miscarriages and elective termination of pregnancies, tissue microarrays were constructed, and then the expression of Gal-13 and Gal-14 was analyzed by immunohistochemistry and immunoscoring. Recombinant Gal-13 and Gal-14 were expressed and purified, and their effects were investigated on primary peripheral blood T cells. The binding of Gal-13 and Gal-14 to T cells and the effects of these galectins on apoptosis, activation marker (CD25, CD71, CD95, HLA-DR) expression and cytokine (IL-1ß, IL-6, IL-8, IL-10, IFNγ) production of T cells were examined by flow cytometry. Gal-13 and Gal-14 are primarily expressed by the syncytiotrophoblast at the maternal-fetal interface in the first trimester, and their placental expression is decreased in miscarriages compared to first-trimester controls. Recombinant Gal-13 and Gal-14 bind to T cells in a population- and activation-dependent manner. Gal-13 and Gal-14 induce apoptosis of Th and Tc cell populations, regardless of their activation status. Out of the investigated activation markers, Gal-14 decreases the cell surface expression of CD71, Gal-13 increases the expression of CD25, and both galectins increase the expression of CD95 on T cells. Non-activated T cells produce larger amounts of IL-8 in the presence of Gal-13 or Gal-14. In conclusion, these results show that Gal-13 and Gal-14 already provide an immunoprivileged environment at the maternal-fetal interface during early pregnancy, and their reduced expression is related to miscarriages.

3.
Orv Hetil ; 160(17): 643-645, 2019 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-31010305
4.
Eur Heart J ; 40(26): 2155-2163, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30957868

RESUMO

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

5.
J Mol Cell Cardiol ; 129: 208-218, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30844361

RESUMO

AIM: Here we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH). METHODS: Abdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes. RESULTS: AB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LV mass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca2+ sensitivity (pCa50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca2+-sensitivity among the study groups. CONCLUSION: Changes in myofilament Ca2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.

6.
Orv Hetil ; 160(12): 473-474, 2019 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-30876385
7.
Molecules ; 24(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736394

RESUMO

Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. Methods: Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. Results: BGP-15 restored diastolic parameters (e'/a', E/e', LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. Conclusions: Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM.


Assuntos
Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Oximas/farmacologia , Piperidinas/farmacologia , Animais , Biomarcadores , Cardiomiopatias Diabéticas/diagnóstico , Cardiomiopatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Ecocardiografia/métodos , Insuficiência Cardíaca Diastólica/diagnóstico , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Testes de Função Cardíaca , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Ratos
8.
Am J Obstet Gynecol ; 220(6): 605, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30771345
9.
Placenta ; 76: 30-39, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30803712

RESUMO

INTRODUCTION: Placental Protein 5 (PP5)/Tissue Factor Pathway Inhibitor-2 (TFPI-2) is an extracellular matrix-associated protein mainly expressed by the syncytiotrophoblast that may regulate trophoblast invasion. Our aim was to study placental PP5/TFPI-2 expression and its relation to placental pathology in various forms of preeclampsia and HELLP syndrome. METHODS: Placental and maternal blood specimens were collected at the time of delivery from the same women in the following groups: 1) early controls; 2) early preeclampsia; 3) early preeclampsia with HELLP syndrome; 4) late controls; and 5) late preeclampsia. After histopathological examination, placental specimens were immunostained with polyclonal anti-PP5/TFPI-2 antibody on Western blot and tissue microarray immunohistochemistry. Placental PP5/TFPI-2 immunoscores were assessed manually and with a semi-automated method. Maternal sera were immunoassayed for PP5/TFPI-2. RESULTS: PP5/TFPI-2 was localized to the cytoplasm of syncytiotrophoblast. Manual and semi-automated PP5/TFPI-2 immunoscores were higher in early preeclampsia with or without HELLP syndrome but not in late preeclampsia than in respective controls. In patients with preeclampsia, the correlation of placental PP5/TFPI-2 expression with maternal vascular malperfusion score of the placenta was positive while it was negative with birthweight and placental weight. Maternal serum PP5/TFPI-2 concentration was higher in early preeclampsia and it tended to be higher in early preeclampsia with HELLP syndrome than in early controls. DISCUSSION: Our findings suggest that an increased placental PP5/TFPI-2 expression may be associated with abnormal placentation in early preeclampsia, with or without HELLP syndrome.

10.
Sci Rep ; 9(1): 4, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626909

RESUMO

The complex effects of estradiol on non-reproductive tissues/cells, including lymphoid tissues and immunocytes, have increasingly been explored. However, the role of sex hormone binding globulin (SHBG) in the regulation of these genomic and non-genomic actions of estradiol is controversial. Moreover, the expression of SHBG and its internalization by potential receptors, as well as the influence of SHBG on estradiol uptake and signaling in lymphocytes has remained unexplored. Here, we found that human and mouse T cells expressed SHBG intrinsically. In addition, B lymphoid cell lines as well as both primary B and T lymphocytes bound and internalized external SHBG, and the amount of plasma membrane-bound SHBG decreased in B cells of pregnant compared to non-pregnant women. As potential mediators of this process, SHBG receptor candidates expressed by lymphocytes were identified in silico, including estrogen receptor (ER) alpha. Furthermore, cell surface-bound SHBG was detected in close proximity to membrane ERs while highly colocalizing with lipid rafts. The SHBG-membrane ER interaction was found functional since SHBG promoted estradiol uptake by lymphocytes and subsequently influenced Erk1/2 phosphorylation. In conclusion, the SHBG-SHBG receptor-membrane ER complex participates in the rapid estradiol signaling in lymphocytes, and this pathway may be altered in B cells in pregnant women.

12.
ESC Heart Fail ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30378288

RESUMO

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first-in-class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double-blind, placebo-controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time-averaged proportional change in N-terminal pro-brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.

14.
Eur Heart J ; 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30295807

RESUMO

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

16.
Int J Mol Sci ; 19(10)2018 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-30249014

RESUMO

Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a rabbit model that shows cardiac dysfunction as a result of an atherogenic diet, and examined the myocardial PDE9A signaling. Rabbits were divided into Control (normal diet) and HC (atherogenic diet) groups. Cardiac function was evaluated by echocardiography. Vascular function was assessed, along with serum biomarkers. Histological stains were conducted, expression of selected proteins and cyclic guanosine monophosphate (cGMP) levels were determined. Signs of diastolic dysfunction were shown in HC animals, along with concentric hypertrophy and interstitial fibrosis. Endothelial function was diminished in HC rabbits, along with marked reduction in the aortic lumen, and increased left ventricle outflow tract (LVOT) pressures. A significant increase was shown in myocardial PDE9A levels in HC animals with unchanged vasodilator-stimulated phosphoprotein (VASP) phosphorylation and cGMP levels. Upregulation of PDE9A may be associated with early stage of cardiac dysfunction in atherosclerotic conditions. Since PDE9A is involved in cGMP degradation and in deactivation of the cardioprotective PKG signaling pathway, it may become an encouraging target for future investigations in atherosclerotic diseases.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30077797

RESUMO

There is a growing body of evidence that poly(ADP-ribose) polymerase-2 (PARP2), although originally described as a DNA repair protein, has a widespread role as a metabolic regulator. We show that the ablation of PARP2 induced characteristic changes in the lipidome. The silencing of PARP2 induced the expression of sterol regulatory element-binding protein-1 and -2 and initiated de novo cholesterol biosynthesis in skeletal muscle. Increased muscular cholesterol was shunted to muscular biosynthesis of dihydrotestosterone, an anabolic steroid. Thus, skeletal muscle fibers in PARP2-/- mice were stronger compared to those of their wild-type littermates. In addition, we detected changes in the dynamics of the cell membrane, suggesting that lipidome changes also affect the biophysical characteristics of the cell membrane. In in silico and wet chemistry studies, we identified lipid species that can decrease the expression of PARP2 and potentially phenocopy the genetic abruption of PARP2, including artificial steroids. In view of these observations, we propose a new role for PARP2 as a lipid-modulated regulator of lipid metabolism.

18.
Front Immunol ; 9: 1661, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30135684

RESUMO

Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

19.
J Neurosci ; 38(35): 7683-7700, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30054395

RESUMO

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in postmitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMAs) and the presence of this posttranslational modification provides protection against environmental stress. We identify protein arginine methyltransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in postmitotic neurons. Male PRMT8 knock-out mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the cAMP response-element-binding protein 1 (CREB1) level. As a consequence, the expression of CREB1-mediated prosurvival and regeneration-associated immediate early genes is dysregulated in aging PRMT8 knock-out mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived postmitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration.SIGNIFICANCE STATEMENT Although most of the cells in our body have a very short lifespan, postmitotic neurons must survive for many decades. Longevity of a cell within the organism depends on its ability to properly regulate signaling pathways that counteract perturbations, such as DNA damage, oxidative stress, or protein misfolding. Here, we provide evidence that tissue-specific regulators of stress tolerance exist in postmitotic neurons. Specifically, we identify protein arginine methyltransferase 8 (PRMT8) as a cell-type-restricted arginine methyltransferase in spinal cord motoneurons (MNs). PRMT8-dependent arginine methylation is required for neuroprotection against age-related increased of cellular stress. Tissue-restricted expression and the enzymatic activity of PRMT8 make it an attractive target for drug development to delay the onset of neurodegenerative disorders.

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