Inhibition of matrix metalloproteinase-2 improves endothelial function and prevents hypertension in insulin-resistant rats

BACKGROUND AND PURPOSE

Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90).

EXPERIMENTAL APPROACH

We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance.

KEY RESULTS

Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity.

CONCLUSIONS AND IMPLICATIONS

Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.     

Heparanase promotes the spontaneous metastasis of myeloma cells to bone

Although widespread skeletal dissemination is a critical step in the progression of myeloma, little is known regarding mechanisms that control metastasis of this cancer. Heparanase-1 (heparanase), an enzyme that cleaves heparan sulfate chains, is expressed at high levels in some patients with myeloma and promotes metastasis of some tumor types (eg, breast, lymphoma). Using a severe combined immunodeficient (SCID) mouse model, we demonstrate that enhanced expression of heparanase by myeloma cells dramatically up-regulates their spontaneous metastasis to bone. This occurs from primary tumors growing subcutaneously and also from primary tumors established in bone. Interestingly, tumors formed by subcutaneous injection of cells metastasize not only to bone, but also to other sites including spleen, liver, and lung. In contrast, tumors formed by injection of cells directly into bone exhibit a restricted pattern of metastasis that includes dissemination of tumor to other bones but not to extramedullary sites. In addition, expression of heparanase by myeloma cells (1) accelerates the initial growth of the primary tumor, (2) increases whole-body tumor burden as compared with controls, and (3) enhances both the number and size of microvessels within the primary tumor. These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo.     

Does alcohol increase the risk of overdose death: the need for a translational approach

Background We argue for a translational approach to addiction science, using an important current research question as a case study. Case study What is the evidence in support of the hypothesis that alcohol increases the risk of a heroin/opiate overdose through a pharmacological interaction? Findings The positive epidemiological evidence shows that opiate overdose deaths rarely involve a single drug; that alcohol is the most common other drug involved; that there is a negative association between alcohol and morphine concentration at post mortem; and that post‐mortem levels of morphine are often below the levels expected of highly tolerant individuals. The evidence is consistent with the hypothesis that heroin users who drink may require less heroin to overdose than those who do not drink (all other factors being equal) because of a pharmacological interaction. However, the evidence is consistent with, and does not rule out, other causal (and non‐causal) pathways. Alcohol could be associated negatively with tolerance, or confounded by other factors. Experimental evidence is required which is unlikely to be obtained through further epidemiological study or through randomized clinical trials. Conclusions We believe that animal models could provide the key evidence to test the hypothesis for a ‘pharmacodynamic’ or ‘pharmacokinetic’ interaction, which could be corroborated in clinical challenge studies and epidemiological studies. Such a translational approach demands greater collaboration between addiction scientists from basic to applied science and from neuroscience to social science, and would be able to address other key research questions and hypotheses in addiction.     

The serious import of humour in health visiting

Using a typical example this paper illustrates how health visitors use humour in child health clinics to introduce subjects on which health visitor and client may have different views.     

Antibiotic susceptabilities of Pseudomonas aeruginosa isolates derived from patients with cystic fibrosis under aerobic, anaerobic, and biofilm conditions

Recent studies have determined that Pseudomonas aeruginosa can live in a biofilm mode within hypoxic mucus in the airways of patients with cystic fibrosis (CF). P. aeruginosa grown under anaerobic and biofilm conditions may better approximate in vivo growth conditions in the CF airways, and combination antibiotic susceptibility testing of anaerobically and biofilm-grown isolates may be more relevant than traditional susceptibility testing under planktonic aerobic conditions. We tested 16 multidrug-resistant isolates of P. aeruginosa derived from CF patients using multiple combination bactericidal testing to compare the efficacies of double and triple antibiotic combinations against the isolates grown under traditional aerobic planktonic conditions, in planktonic anaerobic conditions, and in biofilm mode. Both anaerobically grown and biofilm-grown bacteria were significantly less susceptible (P < 0.01) to single and combination antibiotics than corresponding aerobic planktonically grown isolates. Furthermore, the antibiotic combinations that were bactericidal under anaerobic conditions were often different from those that were bactericidal against the same organisms grown as biofilms. The most effective combinations under all conditions were colistin (tested at concentrations suitable for nebulization) either alone or in combination with tobramycin (10 microg ml(-1)), followed by meropenem combined with tobramycin or ciprofloxacin. The findings of this study illustrate that antibiotic sensitivities are dependent on culture conditions and highlight the complexities of choosing appropriate combination therapy for multidrug-resistant P. aeruginosa in the CF lung.     

Individual variation in rapid eye movement sleep is associated with pain perception in healthy women: preliminary data

STUDY OBJECTIVES: Sleep-deprivation experiments suggest that sleep loss increases pain sensitivity. It is unclear from preliminary studies, however, whether sleep-related processes are directly associated with pain perception or whether hyperalgesia is due to the secondary effects of sleep deprivation and/or demand characteristics. Consequently, we sought to evaluate relationships between sleep architecture and laboratory measures of pain processing in healthy women, sleeping under normal conditions. DESIGN: Correlational, 2-night polysomnographic study with laboratory pain testing conducted on subsequent days. SETTING: General clinical research center inpatient unit with private room. PARTICIPANTS: Sixteen healthy, female, pain-free good sleepers, free from centrally acting agents (mean age = 24 +/- 4.5 years). MEASUREMENT AND RESULTS: Standard polysomnographic sleep-continuity and architecture variables and subject responses to standard noxious thermal stimuli delivered to the ventral and dorsal surfaces of the forearm via thermal sensory analyzer. Ratings of thermal pain threshold as well as suprathreshold indices of central pain processing (mean/peak ratings and intensity of painful aftersensations) were obtained. Averaging across nights/days, we found significant negative relationships between rapid eye movement sleep latency and suprathreshold pain ratings, ie, measures of heightened central pain processing (r = -.64 to -.73, P < .01). Significant positive relationships were also found between percentage of rapid eye movement sleep and suprathreshold ratings(r = .56 to .66, P < .050). CONCLUSIONS: These data are the first to demonstrate a relationship between individual variation in rapid eye movement sleep and pain-modulatory processes. The results have implications for the etiology of pain disorders and suggest that neurobiologic substrates regulating sleep may also play a role in central pain processing.     

Nociceptive flexion reflex thresholds and pain during rest and computer game play in patients with hypertension and individuals at risk for hypertension

Supraspinal pain modulation may explain hypertensive hypoalgesia. We compared nociceptive flexion reflex (NFR) thresholds and pain during rest and computer game play in hypertensives and normotensives (Experiment 1) and normotensives with and without hypertensive parents (Experiment 2). The game was selected to modulate activity in pain pathways. NFR thresholds did not differ between groups during rest or game play. Pain ratings never differed between hypertensives and normotensives, whereas individuals with hypertensive parents reported less pain during the first two NFR assessments, compared to those without. NFR thresholds and pain were reduced by game play compared to rest. The failure of game play to differentially modulate NFR thresholds or associated pain reports between groups argues against enhanced supraspinal modulation of nociception and pain in hypertensives and those at increased risk for hypertension.     

HIV reservoirs and latency models

The main impediment to a cure for HIV is the existence of long-lasting treatment resistant viral reservoirs. In this review, we discuss what is currently known about reservoirs, including their formation and maintenance, while focusing on latently infected CD4+ T cells. In addition, we compare several different in vivo and in vitro models of latency. We comment on how each model may reflect the properties of reservoirs in vivo, especially with regard to cell phenotype, since recent studies demonstrate that multiple CD4+ T cell subsets contribute to HIV reservoirs and that with HAART and disease progression the relative contribution of different subsets may change. Finally, we focus on the direct infection of resting CD4+ T cells as a source of reservoir formation and as a model of latency, since recent results help explain the misconception that resting CD4+ T cells appeared to be resistant to HIV in vitro.     

Prevalence of human papillomavirus genotypes and associated cervical squamous intraepithelial lesions in HIV-infected women in Botswana

Human papillomaviruses (HPV) constitute one of the most prevalent sexually transmitted infections and are the etiological agents for invasive cervical cancer, the predominant cancer among women in Botswana. However, the prevalence of HPV genotypes in Botswana has yet to be reported. One hundred thirty‐nine endocervical swabs were taken at baseline from HIV‐1 infected, HSV‐2 seropositive women enrolled in a longitudinal cohort study designed to assess the influence of herpes simplex virus‐2 (HSV‐2) infection on genital tract shedding of HIV‐1. Extracted DNA was evaluated for the presence of low‐risk and high‐risk HPV using the Roche Linear Array. Genotyping identified HPV in 95 of 139 women of which 61/95 were infected with high‐risk HPV and 56/95 with low‐risk HPV. The median number of genotypes was 2 (IQR: 1–4). The most prevalent HPV genotype in HIV‐infected women was HPV 58. Abnormal cervical cytology was detected in 87/127 women and was associated with contemporaneous HPV infection (RR = 1.43, 95% CI: 1.05–1.93; P = 0.02). HPV prevalence was high among HIV‐infected women with infection by multiple genotypes being widespread. The associations attributed to specific oncogenic HPV subtypes and cervical squamous intraepithelial lesions presented here provide critical information to inform future vaccine policy within Botswana. J. Med. Virol. 83:1689–1695, 2011. © 2011 Wiley‐Liss, Inc.