Lysophospholipids in coronary artery and chronic ischemic heart disease.

PURPOSE OF REVIEW: The bioactive lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P), have potent effects on blood and vascular cells. This review focuses their potential contributions to the development of atherosclerosis, acute complications such as acute myocardial infarction, and chronic ischemic cardiac damage. RECENT FINDINGS: Exciting recent developments have provided insight into the molecular underpinnings of LPA and S1P receptor signaling. New lines of evidence suggest roles for these pathways in the development of atherosclerosis. In experimental animal models, the production, signaling, and metabolism of LPA may be influenced by environmental factors in the diet that synergize to promote the progression of atherosclerotic vascular disease. This is supported by observations of human polymorphisms in the lysophospholipid-metabolizing enzyme PPAP2B, which are associated with risk of coronary artery disease and myocardial infarction. S1P signaling protects from myocardial damage that follows acute and chronic ischemia, both by direct effects on cardiomyocytes and through stem cell recruitment to ischemic tissue. SUMMARY: This review will suggest novel strategies to prevent the complications of coronary artery disease by targeting LPA production and signaling. Additionally, ways in which S1P signaling pathways may be harnessed to attenuate ischemia-induced cardiac dysfunction will be explored.

Activity-dependent genes in mouse olfactory sensory neurons.

Activity-dependent survival of olfactory sensory neurons (OSNs) may allow animals to tune their olfactory systems to match their odor environment. Activity-dependent genes should play important roles in this process, motivating experiments to identify them. Both unilateral naris occlusion of mice for 6 days and genetic silencing of OSNs decreased S100A5, Lrrc3b, Kirrel2, Slc17a6, Rasgrp4, Pcp4l1, Plcxd3, and Kcnn2 while increasing Kirrel3. Naris occlusion also decreased Eml5, Ptprn, and Nphs1. OSN number was unchanged and stress-response mRNAs were unaffected after 6 days of naris occlusion. This leaves odor stimulation as the most likely cause of differential abundance of these mRNAs, but through a mechanism that is slow or indirect for most because 30-40 min of odor stimulation increased only 3 of 11 mRNAs decreased by naris occlusion: S100A5, Lrrc3b, and Kirrel2. Odorant receptor (OR) mRNAs were significantly more variable than the average mRNA, consistent with difficulty in reliably detecting changes in these mRNAs after 6 days of naris occlusion. One OR mRNA, Olfr855, was consistently decreased, however. These results suggest that the latency from the cessation of odor stimulation to effects on activity-dependent OSN survival must be a week or more in juvenile mice.

Targeting sensory axon regeneration in adult spinal cord.

Extensive regeneration of sensory axons into the spinal cord can be achieved experimentally after dorsal root injury, but no effort has been made to target regenerating axons and restore a normal lamina-specific projection pattern. Ectopic axon growth is potentially associated with functional disorders such as chronic pain and autonomic dysreflexia. This study was designed to target regenerating axons to normal synaptic locations in the spinal cord by combining positive and negative guidance molecules. Previously, we observed that, after dorsal rhizotomy, overexpression of NGF leads to robust regeneration and sprouting of calcitonin gene-related peptide (CGRP)-positive nociceptive axons throughout dorsal horn and ventral horns. To restrict these axons within superficial laminas, adenovirus expressing semaphorin 3A was injected into the ventral spinal cord 3 d after NGF virus injection. Semaphorin 3A expression was observed in deep dorsal and ventral cord regions and limited axon growth to laminas I and II, shaping axonal regeneration toward the normal distribution pattern. NGF and semaphorin 3A treatment also targeted the regeneration of substance P-positive nociceptive axons but had no effect on injured isolectin B4-binding nociceptive axons. Axon regeneration led to functional restoration of nociception in both NGF- and NGF/semaphorin 3A-treated rats. Although no significant difference in behavior was found between these two groups, confocal microscopy illustrated ectopic synaptic formations in deeper laminas in NGF/green fluorescent protein-treated rats. The results suggested that antagonistic guidance cues can be used to induce and refine regeneration within the CNS, which is important for long-term, optimal functional recovery.

Obesity and Antiplatelets-Does One Size Fit All?

Antiplatelet therapy has become a cornerstone in the management of many vascular diseases. With growing antiplatelet options, attention has focused on their comparative effectiveness in specific patient populations. Perhaps one of the least defined factors influencing efficacy of these agents is body mass and obesity. Evidence from preclinical models established that obesity promotes inflammation that in turn enhances platelet reactivity. Thus, adiposity has the potential to diminish or alter the therapeutic effect of antiplatelet therapy. Pharmacodynamic analyses suggest a potential need for dose adjustments of antiplatelet therapy in obese patients. Yet, obese patients paradoxically have better outcomes after acute coronary syndromes. In this review, we identify a critical need for clinical studies with outcome data to enable the development of recommendations for optimal antiplatelet regimens in obese individuals. Until such data exists, healthcare providers should be aware of the potential impact of obesity on the efficacy of anti-platelet therapy.

Molecular events in the cell types of the olfactory epithelium during adult neurogenesis.

BACKGROUND: Adult neurogenesis, fundamental for cellular homeostasis in the mammalian olfactory epithelium, requires major shifts in gene expression to produce mature olfactory sensory neurons (OSNs) from multipotent progenitor cells. To understand these dynamic events requires identifying not only the genes involved but also the cell types that express each gene. Only then can the interrelationships of the encoded proteins reveal the sequences of molecular events that control the plasticity of the adult olfactory epithelium. RESULTS: Of 4,057 differentially abundant mRNAs at 5 days after lesion-induced OSN replacement in adult mice, 2,334 were decreased mRNAs expressed by mature OSNs. Of the 1,723 increased mRNAs, many were expressed by cell types other than OSNs and encoded proteins involved in cell proliferation and transcriptional regulation, consistent with increased basal cell proliferation. Others encoded fatty acid metabolism and lysosomal proteins expressed by infiltrating macrophages that help scavenge debris from the apoptosis of mature OSNs. The mRNAs of immature OSNs behaved dichotomously, increasing if they supported early events in OSN differentiation (axon initiation, vesicular trafficking, cytoskeletal organization and focal adhesions) but decreasing if they supported homeostatic processes that carry over into mature OSNs (energy production, axon maintenance and protein catabolism). The complexity of shifts in gene expression responsible for converting basal cells into neurons was evident in the increased abundance of 203 transcriptional regulators expressed by basal cells and immature OSNs. CONCLUSIONS: Many of the molecular changes evoked during adult neurogenesis can now be ascribed to specific cellular events in the OSN cell lineage, thereby defining new stages in the development of these neurons. Most notably, the patterns of gene expression in immature OSNs changed in a characteristic fashion as these neurons differentiated. Initial patterns were consistent with the transition into a neuronal morphology (neuritogenesis) and later patterns with neuronal homeostasis. Overall, gene expression patterns during adult olfactory neurogenesis showed substantial similarity to those of embryonic brain.

Estrogen receptor alpha inhibits the estrogen-mediated suppression of HIV transcription in astrocytes: implications for estrogen neuroprotection in HIV dementia.

Many human immunodeficiency virus (HIV) proteins including Tat are produced by HIV-infected astrocytes and secreted into the brain resulting in extensive neuronal damage that contributes to the pathogenesis of HIV dementia. The neuroprotective hormone 17beta-estradiol (E2) is known to negatively regulate the HIV transcriptional promoter in human fetal astrocytes (SVGA cell line) in a Tat-dependent manner. In the present study we extended our investigation in HIV-infected SVGA cells and found a reduction in HIV p24 levels following E2 treatment in comparison to control. Although many E2-mediated events occur through estrogen receptor alpha (ERalpha), we found low levels of ERalpha mRNA and failed to detect ERalpha protein in SVGA cells. Paradoxically, when ERalpha was overexpressed the E2-mediated decrease in Tat transactivation of the promotor was prevented. To determine whether ERalpha expression is altered in the human brain following HIV infection, postmortum hippocampal tissue was obtained from cognitively normal HIV- and HIV+ patients, patients diagnosed with either mild cognitive/motor disorder (MCMD) or HIV-associated dementia (HAD). Immunohistochemistry and quantitative real-time PCR (qRT-PCR) for ERalpha and glial fibrillary acidic protein (GFAP) showed that ERalpha mRNA levels were not significantly different between groups, while GFAP increased in the hippocampus in the HIV+ compared to the HIV- group and was decreased in the MCMD and HAD subgroups compared to HIV+ controls. Notably the ratio of ERalpha-positive reactive astrocytes to total reactive astrocytes increased and significantly correlated with the severity of cognitive impairment following HIV infection. The data suggest that E2 would have the most dramatic effect in reducing HIV transcription early in the disease process when the subpopulation of astrocytes expressing ERalpha is low.