HIV-1 Tat protein stimulates in vivo vascular permeability and lymphomononuclear cell recruitment

HIV-1 Tat protein released by infected cells is a chemotactic molecule for leukocytes and induces a proinflammatory program in endothelial cells (EC) by activating vascular endothelial growth factor (VEGF) receptors expressed on both cell types. Its potential role in causing vascular permeability and leukocyte recruitment was studied in vivo following its s.c. injection in mice. Tat caused a dose-dependent early (15 min) and late (6 h) wave of permeability that were inhibited by a neutralizing Ab anti-VEGF receptor type 2. Tissue infiltration of lymphomononuclear cells, mainly monocytes (76%), was evident at 6 h and persisted up to 24 h. WEB2170, a platelet activating factor (PAF) receptor antagonist, reduced the early leakage by 70-80%, but only slightly inhibited the late wave and cell recruitment. In vitro, Tat induced a dose-dependent flux of albumin through the EC monolayer that was inhibited by Ab anti-vascular VEGF receptor type 2 and WEB2170, and PAF synthesis in EC that was blocked by the Ab anti-VEGF receptor type 2. Lastly, an anti-monocyte chemotactic peptide-1 (MCP-1) Ab significantly reduced the lymphomononuclear infiltration elicited by Tat. In vitro, Tat induced a dose-dependent production of MCP-1 by EC after a 24-h stimulation. These results highlighted the role of PAF and MCP-1 as secondary mediators in the onset of lymphomononuclear cell recruitment in tissues triggered by Tat.     

A comparison of balloon injury models of endovascular lesions in rat arteries

Background

Balloon injury (BI) of the rat carotid artery (CCA) is widely used to study intimal hyperplasia (IH) and decrease in lumen diameter (LD), but CCA's small diameter impedes the evaluation of endovascular therapies. Therefore, we validated BI in the aorta (AA) and iliac artery (CIA) to compare it with CCA.

Methods

Rats underwent BI or a sham procedure (control). Light microscopic evaluation was performed either directly or at 1, 2, 3, 4 and 16 weeks follow-up. The area of IH and the change in LD (LD at 16 weeks minus LD post BI) were compared.

Results

In the BI-groups the area of IH increased to 0.14 ± 0.08 mm² (CCA), 0.14 ± 0.03 mm² (CIA) and 0.12 ± 0.04 mm² (AA) at 16 weeks (NS). The LD decreased with 0.49 ± 0.07 mm (CCA), compared to 0.22 ± 0.07 mm (CIA) and 0.07 ± 0.10 mm (AA) at 16 weeks (p < 0.05). The constrictive vascular remodelling (CVR = wall circumference loss combined with a decrease in LD) was -0.17 ± 0.05 mm in CIA but absent in CCA and AA. No IH, no decrease in LD and no CVR was seen in the control groups.

Conclusions

BI resulted in: (1.) a decrease in LD in CCA due to IH, (2.) a decrease in LD in CIA due to IH and CVR, (3.) no change in LD in AA, (4.) Comparable IH development in all arteries, (5.) CCA has no vasa vasorum compared to CIA and AA, (6.) The CIA model combines good access for 2 F endovascular catheters with a decrease in LD due to IH and CVR after BI.     

Increased Na pump activity in the kidney cortex of the Milan hypertensive rat strain

The (Na+,K+)-ATPase activity from the kidney cortex of the Milan hypertensive rat strain (MHS) and the corresponding normotensive control (MNS) was measured both in active solubilized enzyme preparations and in isolated basolateral membrane vesicles. Kinetic analysis of the purified enzyme showed that the Vmax value was significantly higher in MHS rats. The difference between MHS and MNS was not linked to a different number of sodium pumps, but was related to the molecular activity of the enzyme. Using basolateral membrane vesicles, an increased ATP-dependent ouabain-sensitive sodium transport was also demonstrated in MHS rats. These results support the hypothesis that a higher tubular sodium reabsorption may be involved in the pathogenesis of hypertension in this rat strain.     

Lack of Salt-Inducible Kinase 2 (SIK2) Prevents the Development of Cardiac Hypertrophy in Response to Chronic High-Salt Intake

Cardiac left ventricle hypertrophy (LVH) constitutes a major risk factor for heart failure. Although LVH is most commonly caused by chronic elevation in arterial blood pressure, reduction of blood pressure to normal levels does not always result in regression of LVH, suggesting that additional factors contribute to the development of this pathology. We tested whether genetic preconditions associated with the imbalance in sodium homeostasis could trigger the development of LVH without concomitant increases in blood pressure. The results showed that the presence of a hypertensive variant of α-adducin gene in Milan rats (before they become hypertensive) resulted in elevated expression of genes associated with LVH, and of salt-inducible kinase 2 (SIK2) in the left ventricle (LV). Moreover, the mRNA expression levels of SIK2, α-adducin, and several markers of cardiac hypertrophy were positively correlated in tissue biopsies obtained from human hearts. In addition, we found in cardiac myocytes that α-adducin regulates the expression of SIK2, which in turn mediates the effects of adducin on hypertrophy markers gene activation. Furthermore, evidence that SIK2 is critical for the development of LVH in response to chronic high salt diet (HS) was obtained in mice with ablation of the sik2 gene. Increases in the expression of genes associated with LVH, as well as increases in LV wall thickness upon HS, occurred only in sik2^+/+ but not in sik2^−/− mice. Thus LVH triggered by HS or the presence of a genetic variant of α-adducin requires SIK2 and is independent of elevated blood pressure. Inhibitors of SIK2 may constitute part of a novel therapeutic regimen aimed at prevention/regression of LVH.     

Organ hypertrophic signaling within caveolae membrane subdomains triggered by ouabain and antagonized by PST 2238

In addition to inhibition of the Na-K ATPase, ouabain activates a signal transduction function, triggering growth and proliferation of cultured cells even at nanomolar concentrations. An isomer of ouabain (EO) circulates in mammalians at subnanomolar concentrations, and increased levels are associated with cardiac hypertrophy and hypertension. We present here a study of cardiac and renal hypertrophy induced by ouabain infused into rats for prolonged periods and relate this effect to the recently described ouabain-induced activation of the Src-EGFr-ERK signaling pathway. Ouabain infusion into rats (15 microg/kg/day for 18 weeks) doubled plasma ouabain levels from 0.3 to 0.7 nm and increased blood pressure by 20 mm Hg (p < 0.001), cardiac left ventricle (+11%, p < 0.05), and kidney weight (+9%, p < 0.01). These effects in vivo are associated with a significant enrichment of alpha1, beta1, gammaa Na-K ATPase subunits together with Src and EGFr in isolated renal caveolae membranes and activation of ERK1/2. In caveolae, direct Na-K ATPase/Src interactions can be demonstrated by co-immunoprecipitation. The interaction is amplified by ouabain, at a high affinity binding site, detectable in caveolae but not in total rat renal membranes. The high affinity site for ouabain is associated with Src-dependent tyrosine phosphorylation of rat alpha1 Na-K ATPase. The antihypertensive compound, PST 2238, antagonized all ouabain-induced effects at 10 microg/kg/day in vivo or 10(-10)-10(-8) m in vitro. These findings provide a molecular mechanism for the in vivo pro-hypertrophic and hypertensinogenic activity of ouabain, or by analogy those of EO in humans. They also explain the pharmacological basis for PST 2238 treatment.     

Activation of morphogenesis and proliferation by low specificity chemical effectors

Activation of highly specific biochemical processes by simple chemical agents is demonstrated for morphogenesis (anlage and development of female gametophyte in cereal) and mitosis (in cell cultures and animal and plant tissues). The effects of these agents are tissue-specific. Structure--activity relationship is analyzed in this group of compounds. Thus, the phenomenon reveals the exact pathways of the influence of allelopathic and anthropogenic chemical agents on evolution of plant biocenoses.     

Imaging of left main trauma during diagnostic cardiac catheterization with intravascular ultrasound

In this case report the occurrence of a catheter-induced coronary artery dissection is described. In our patient, angiography showed a mushroom-shaped exudate above the left main coronary artery. Intravascular ultrasound revealed a circular dissection with a huge false lumen connected to the true lumen by a small intimal tear. A brief review of the literature on catheter-induced coronary dissection is included. We believe that this case report provides a good illustration of the need for careful reviewing of indications for angiography. Although procedural risks are low, angiography remains an invasive diagnostic test with the potential to cause severe complications.     

Deinococcus radiodurans' SRA-HNH domain containing protein Shp (Dr1533) is involved in faithful genome inheritance maintenance following DNA damage

Background

Deinococcus radiodurans R1 (DR) survives conditions of extreme desiccation, irradiation and exposure to genotoxic chemicals, due to efficient DNA breaks repair, also through Mn²⁺ protection of DNA repair enzymes.