Speckle tracking echocardiography: new ways of translational approaches in preeclampsia to detect cardiovascular dysfunction

Several studies have shown that women with a preeclamptic pregnancy exhibit an increased risk of cardiovascular disease. However, the underlying molecular mechanisms are unknown. Animal models are essential to investigate the causes of this increased risk and have the ability to assess possible preventive and therapeutic interventions. Using the latest technologies such as speckle tracking echocardiography (STE), it is feasible to map subclinical changes in cardiac diastolic and systolic function as well as structural changes of the maternal heart. The aim of this work is to compare cardiovascular changes in an established transgenic rat model with preeclampsia-like pregnancies with findings from human preeclamptic pregnancies by STE. The same algorithms were used to evaluate and compare the changes in echos of human and rodents. Parameters of functionality like global longitudinal strain (animal -23.54 ± 1.82 % vs. -13.79 ± 0.57 %, human -20.60 ± 0.47 % vs. -15.45 ± 1.55 %) as well as indications of morphological changes like relative wall thickness (animal 0.20 ± 0.01 vs. 0.25 ± 0.01, human 0.34 ± 0.01 vs. 0.40 ± 0.02) are significantly altered in both species after preeclamptic pregnancies. Thus, the described rat model simulates the human situation quite well and is a valuable tool for future investigations regarding cardiovascular changes. STE is a unique technique which can be applied in animal models and human with a high potential to uncover cardiovascular maladaptation and subtle pathologies

Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

BACKGROUND: We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-{kappa}B in our model. METHODS: We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats. Blood-pressure- and albuminuria- measurements were monitored during the treatment period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analysis. RESULTS: Chronic treatment with the antioxidant PDTC decreased blood pressure (162 plus minus 8 vs. 190 plus minus 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 plus minus 0.1 vs. 5.77 plus minus 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 plus minus 0.5 vs. 18.0 plus minus 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-{kappa}B binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-{kappa}B subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. CONCLUSION: Our data show that inhibition of NF-{kappa}B by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-{kappa}B activation plays an important role in ANG II-induced end-organ damage

Mononuclear Phagocyte System Depletion Blocks Interstitial Tonicity-Responsive Enhancer Binding Protein/Vascular Endothelial Growth Factor C Expression and Induces Salt-Sensitive Hypertension in Rats

We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na(+) accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na(+) and Cl(-) accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response

One-Way Entangled-Photon Autocompensating Quantum Cryptography

A new quantum cryptography implementation is presented that combines one-way operation with an autocompensating feature that has hitherto only been available in implementations that require the signal to make a round trip between the users. Using the concept of advanced waves, it is shown that this new implementation is related to the round-trip implementations in the same way that Ekert's two-particle scheme is related to the original one-particle scheme of Bennett and Brassard. The practical advantages and disadvantages of the proposed implementation are discussed in the context of existing schemes.Comment: 5 pages, 1 figure; Minor edits--conclusions unchanged; accepted for publication in Physical Review

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA) contribute to the regulation of cardiovascular function. CYP enzymes also accept eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to yield more potent vasodilatory and potentially anti-arrhythmic metabolites, suggesting that the endogenous CYP-eicosanoid profile can be favorably shifted by dietary omega-3 fatty acids. To test this hypothesis, 20 healthy volunteers were treated with an EPA/DHA-supplement and analyzed for concomitant changes in the circulatory and urinary levels of AA-, EPA-, and DHA-derived metabolites produced by the cyclooxygenase-, lipoxygenase- and CYP-dependent pathways. Raising the Omega-3 Index from about 4 to 8 primarily resulted in a large increase of EPA-derived CYP-dependent epoxy-metabolites followed by increases of EPA- and DHA-derived lipoxygenase-dependent monohydroxy-metabolites including the precursors of resolvin E and D families; resolvins themselves were not detected. The metabolite/precursor fatty acid ratios indicated that CYP epoxygenases metabolized EPA with an 8.6-fold and DHA with a 2.2-fold higher efficiency than AA. Effects on leukotriene, prostaglandin E, prostacyclin, and thromboxane formation remained rather weak. We propose that CYP-dependent epoxy-metabolites of EPA and DHA may function as mediators of the vasodilatory and cardioprotective effects of omega-3 fatty acids and could serve as biomarkers in clinical studies investigating the cardiovascular effects of EPA/DHA-supplementation

Manifestation of ageing in the low temperature conductance of disordered insulators

We are interested in the out of equilibrium phenomena observed in the electrical conductance of disordered insulators at low temperature, which may be signatures of the electron coulomb glass state. The present work is devoted to the occurrence of ageing, a benchmark phenomenon for the glassy state. It is the fact that the dynamical properties of a glass depend on its age, i.e. on the time elapsed since it was quench-cooled. We first critically analyse previous studies on disordered insulators and question their interpretation in terms of ageing. We then present new measurements on insulating granular aluminium thin films which demonstrate that the dynamics is indeed age dependent. We also show that the results of different relaxation protocols are related by a superposition principle. The implications of our findings for the mechanism of the conductance slow relaxations are then discussed

Natural killer cell reduction and uteroplacental vasculopathy

Uterine natural killer cells are important for uteroplacental development and pregnancy maintenance. Their role in pregnancy disorders, such as preeclampsia, is unknown. We reduced the number of natural killer cells by administering rabbit anti-asialo GM1 antiserum in an established rat preeclamptic model (female human angiotensinogen×male human renin) and evaluated the effects at the end of pregnancy (day 21), compared with preeclamptic control rats receiving normal rabbit serum. In 100% of the antiserum-treated, preeclamptic rats (7/7), we observed highly degenerated vessel cross sections in the mesometrial triangle at the end of pregnancy. This maternal uterine vasculopathy was characterized by a total absence of nucleated/living cells in the vessel wall and perivascularly and prominent presence of fibrosis. Furthermore, there were no endovascular trophoblast cells within the vessel lumen. In the control, normal rabbit serum-treated, preeclamptic rats, only 20% (1/5) of the animals displayed such vasculopathy. We confirmed the results in healthy pregnant wild-type rats: after anti-asialo GM1 treatment, 67% of maternal rats displayed vasculopathy at the end of pregnancy compared with 0% in rabbit serum-treated control rats. This vasculopathy was associated with a significantly lower fetal weight in wild-type rats and deterioration of fetal brain/liver weight ratio in preeclamptic rats. Anti-asialo GM1 application had no influence on maternal hypertension and albuminuria during pregnancy. Our results show a new role of natural killer cells during hypertensive pregnancy in maintaining vascular integrity. In normotensive pregnancy, this integrity seems important for fetal growth

Magnetically ordered state at correlated oxide interfaces: the role of random oxygen defects

Using an effective one-band Hubbard model with disorder, we consider magnetic states of the correlated oxide interfaces, where effective hole self-doping and a magnetially ordered state emerge due to electronic and ionic reconstructions. By employing the coherent potential approximation, we analyze the effect of random oxygen vacancies on the two-dimensional magnetism. We find that the random vacancies enhance the ferromagnetically ordered state and stabilize a robust magnetization above a critical vacancy concentration of about c=0.1. In the strong-correlated regime, we also obtain a nonmonotonic increase of the magnetization upon an increase of vacancy concentration and a substantial increase of the magnetic moments, which can be realized at oxygen reduced high-Tc cuprate interfaces.Comment: 8 pages, 2 figures, submitted to J Supercond Novel Magnetism (ICSM12 conference contribution

Enhanced Ca(2+) signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1h(M1560V/+))

Gain-of-function mutations in the CACNA1H gene (encoding the T-type calcium channel Ca(V)3.2) cause autosomal-dominant familial hyperaldosteronism type IV (FH-IV) and early-onset hypertension in humans. We used CRISPR/Cas9 to generate Cacna1h(M1560V/+) knockin mice as a model of the most common FH-IV mutation, along with corresponding knockout mice (Cacna1h(-/-)). Adrenal morphology of both Cacna1h(M1560V/+) and Cacna1h(-/-) mice was normal. Cacna1h(M1560V/+) mice had elevated aldosterone:renin ratios (a screening parameter for primary aldosteronism). Their adrenal Cyp11b2 (aldosterone synthase) expression was increased and remained elevated on a high-salt diet (relative autonomy, characteristic of primary aldosteronism), but plasma aldosterone was only elevated in male animals. The systolic blood pressure of Cacna1h(M1560V/+) mice was 8 mmHg higher than in wild-type littermates and remained elevated on a high-salt diet. Cacna1h(-/-) mice had elevated renal Ren1 (renin-1) expression but normal adrenal Cyp11b2 levels, suggesting that in the absence of Ca(V)3.2, stimulation of the renin-angiotensin system activates alternative calcium entry pathways to maintain normal aldosterone production. On a cellular level, Cacna1h(M1560V/+) adrenal slices showed increased baseline and peak intracellular calcium concentrations in the zona glomerulosa compared to controls, but the frequency of calcium spikes did not rise. We conclude that FH-IV, on a molecular level, is caused by elevated intracellular Ca(2+) concentrations as a signal for aldosterone production in adrenal glomerulosa cells. We demonstrate that a germline Cacna1h gain-of-function mutation is sufficient to cause mild primary aldosteronism, whereas loss of Ca(V)3.2 channel function can be compensated for in a chronic setting

Functional diversity of chemokines and chemokine receptors in response to viral infection of the central nervous system.

Encounters with neurotropic viruses result in varied outcomes ranging from encephalitis, paralytic poliomyelitis or other serious consequences to relatively benign infection. One of the principal factors that control the outcome of infection is the localized tissue response and subsequent immune response directed against the invading toxic agent. It is the role of the immune system to contain and control the spread of virus infection in the central nervous system (CNS), and paradoxically, this response may also be pathologic. Chemokines are potent proinflammatory molecules whose expression within virally infected tissues is often associated with protection and/or pathology which correlates with migration and accumulation of immune cells. Indeed, studies with a neurotropic murine coronavirus, mouse hepatitis virus (MHV), have provided important insight into the functional roles of chemokines and chemokine receptors in participating in various aspects of host defense as well as disease development within the CNS. This chapter will highlight recent discoveries that have provided insight into the diverse biologic roles of chemokines and their receptors in coordinating immune responses following viral infection of the CNS