Endogenous Control Mechanisms Research Articles

Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions

Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.

Volume Transmission of Substance P in Striatum Induced by Intraplantar Formalin Injection Attenuates Nociceptive Responses via Activation of the Neurokinin 1 Receptor

To clarify a role of substance P (SP) in an endogenous pain control mechanism involving the rat striatum, striatal SP release was measured over time by microdialysis following intraplantar injection of 0.4% formalin. A slow-onset but significant increase of SP and neurokinin 1 receptor (NK1R) internalization in the contralateral striatum were observed following the second phase of formalin-induced nociceptive behaviors. Moreover, 60 min after formalin injection, preprotachykinin-A, the SP mRNA, and the immediate early gene cFOS were upregulated in the contralateral striatum. Continuous infusion of SP into the striatum by reverse microdialysis attenuated formalin-induced second phase, but not the first phase, nociceptive behaviors, and hind paw mechanical allodynia. Moreover, these anti-nociceptive effects of SP were completely inhibited by co-treatment with the NK1R antagonist CP96345. Acute microinjection of SP, however, at a dose that was similar to the total dose of SP continuously infused into the striatum, did not affect formalin-induced nociceptive behaviors. These data indicate that striatal NK1R activation leads to pain suppression rather than facilitation. Furthermore, volume transmission of SP in the striatum appears to be indispensable in the mechanism of pain control. Modulation of striatal NK1Rs could prove to be a useful method of inducing analgesia.

Dietary restriction supports peripheral nerve health by enhancing endogenous protein quality control mechanisms

The peripheral nervous system (PNS) comprises of an extensive network of connections that convey information between the central nervous system (CNS) and peripheral organs. Long myelinated nerve fibers are particularly susceptible to age-related changes, as maintenance of the insulating glial membrane requires extensive synthesis and processing of many proteins. In rodent models, peripheral demyelination caused by genetic risk factors or by normal aging are attenuated by intermittent fasting (IF) or calorie restriction (CR) supporting a role for dietary intervention in preserving neural function. This review will summarize recent studies examining mechanisms by which life-long CR or extended IF supports peripheral nerve health.

Endocannabinoid‐dependent plasticity at spinal nociceptor synapses

Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB)1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long-term depression (LTD)of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB(1) receptor-deficient mice (CB(1) (−/− ) mice and sns-CB(1)(−/−) mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB1 receptor antagonist AM251 and mimicked by pharmacological activation of CB1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB(1) receptors in CB(1)(−/−) and sns-CB(1)(−/−) mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hither to unknown function of CB1 receptors in primary nociceptors. Both findings may have important implications for our understanding of endogenous pain control mechanisms and of analgesia evoked by cannabinoid receptor agonists.

Extraneuronal activities and regulatory mechanisms of the atypical cyclin-dependent kinase Cdk5

Cyclin-dependent kinase, Cdk5, is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases with no evident role in cell cycle progression. Cdk5 is present in post-mitotic and terminally differentiated neuronal/glial cells and is also known to arrest cell cycle. Also atypical is the activation of Cdk5 by binding of a non-cyclin activator protein, namely, the Cdk5 regulatory proteins Cdk5R1 (p35), truncated Cdk5R1 (p25), or Cdk5R2 (p39). Despite its ubiquitous presence in all cells and tissues, Cdk5 is often referred to as a neuron-specific kinase largely due to the abundant presence of the activator proteins in neuronal cells. Recently, this concept of a canonical neuronal function of Cdk5 has been extended, if not challenged, by the observation of p35 and p39 expression, as well as Cdk5 activity, in multiple non-neuronal cells. Extraneuronal Cdk5 regulates critical biological processes including transcript-selective translation control for regulation of macrophage gene expression, glucose-inducible insulin secretion, hematopoietic cell differentiation, vascular angiogenesis, cell migration, senescence, and wound-healing, among others. Recent advances in the extraneuronal functions of Cdk5 are reviewed and discussed here in the context of their physiological activities and pathophysiological implications with some speculative comments on the endogenous control mechanisms that might “turn on” Cdk5 activity. The potential importance of targeted inhibition of Cdk5 as therapeutic agents against glucotoxicity, diabetes, cardiovascular diseases, and cancer is also discussed.

Effects of perceived and exerted pain control on neural activity during pain relief in experimental heat hyperalgesia: A fMRI study

Perceived control over pain can attenuate pain perception by mechanisms of endogenous pain control and emotional reappraisal irrespective of whether this control is exerted or only perceived. Self-initiated termination of pain elicits different expectations of subsequent pain relief as compared to perceived pain control. It is unknown whether and how this perceived vs. exerted control on pain differs and affects subsequent pain relief. Using fMRI, we studied two factors of pain control on pain relief: the (i) sense of control (perceived control but no execution) and (ii) the execution of control (exerted control). To account for the impact of factual execution of pain control on pain relief we applied bearable short and hardly bearable long contact-heat stimuli which were applied either controllable or not. Using controllability as factor, there was dissociable neural activity during pain relief: following the perceived control condition neural activity was found in the orbitofrontal and mediofrontal cortex and, following the exerted control condition, in the anterolateral and dorsolateral prefrontal cortex and posterior parietal cortex. We conclude that (i) pain controllability has an impact on pain relief and (ii) the prefrontal cortex shows dissociable neural activity during pain relief following exerted vs. perceived pain control. This might reflect the higher grade of uncertainty during pain relief following perceived pain control mediated by the orbitofrontal and medial prefrontal cortex and processes of working memory and updating expectations during pain relief following exerted control mediated by the lateral prefrontal cortex.

Maspin increases Ku70 acetylation and Bax-mediated cell death in cancer cells

Ku70, a DNA repair protein, was recently identified as a critical anti-apoptotic protein that inhibits Bax translocation to mitochondria. The dissociation of Bax from Ku70 is essential for the apoptotic activity of Bax. Here, we show that maspin, a tumor suppressor protein frequently lost in cancer, regulates this process. Maspin increased cell death in a Ku70 acetylation-dependent manner. Maspin inhibited histone deacetylase 1 (HDAC1) and thus increased the acetylation of Ku70 and the dissociation of Bax from Ku70, which led to the induction of apoptosis. These results reveal maspin as a Ku70-interacting molecule and provide the basis for a new endogenous acetylation-based control mechanism that reduces Ku70-mediated sequestration of Bax from mitochondria.

The annual cycle of a trans-equatorial Eurasian–African passerine migrant: different spatio-temporal strategies for autumn and spring migration

The small size of the billions of migrating songbirds commuting between temperate breeding sites and the tropics has long prevented the study of the largest part of their annual cycle outside the breeding grounds. Using light-level loggers (geolocators), we recorded the entire annual migratory cycle of the red-backed shrike Lanius collurio, a trans-equatorial Eurasian-African passerine migrant. We tested differences between autumn and spring migration for nine individuals. Duration of migration between breeding and winter sites was significantly longer in autumn (average 96 days) when compared with spring (63 days). This difference was explained by much longer staging periods during autumn (71 days) than spring (9 days). Between staging periods, the birds travelled faster during autumn (356 km d(-1)) than during spring (233 km d(-1)). All birds made a protracted stop (53 days) in Sahelian sub-Sahara on southbound migration. The birds performed a distinct loop migration (22 000 km) where spring distance, including a detour across the Arabian Peninsula, exceeded the autumn distance by 22 per cent. Geographical scatter between routes was particularly narrow in spring, with navigational convergence towards the crossing point from Africa to the Arabian Peninsula. Temporal variation between individuals was relatively constant, while different individuals tended to be consistently early or late at different departure/arrival occasions during the annual cycle. These results demonstrate the existence of fundamentally different spatio-temporal migration strategies used by the birds during autumn and spring migration, and that songbirds may rely on distinct staging areas for completion of their annual cycle, suggesting more sophisticated endogenous control mechanisms than merely clock-and-compass guidance among terrestrial solitary migrants. After a century with metal-ringing, year-round tracking of long-distance migratory songbirds promises further insights into bird migration.

Challenging claims in the study of migratory birds and climate change

Recent shifts in phenology in response to climate change are well established but often poorly understood. Many animals integrate climate change across a spatially and temporally dispersed annual life cycle, and effects are modulated by ecological interactions, evolutionary change and endogenous control mechanisms. Here we assess and discuss key statements emerging from the rapidly developing study of changing spring phenology in migratory birds. These well-studied organisms have been instrumental for understanding climate-change effects, but research is developing rapidly and there is a need to attack the big issues rather than risking affirmative science. Although we agree poorly on the support for most claims, agreement regarding the knowledge basis enables consensus regarding broad patterns and likely causes. Empirical data needed for disentangling mechanisms are still scarce, and consequences at a population level and on community composition remain unclear. With increasing knowledge, the overall support ('consensus view') for a claim increased and between-researcher variability in support ('expert opinions') decreased, indicating the importance of assessing and communicating the knowledge basis. A proper integration across biological disciplines seems essential for the field's transition from affirming patterns to understanding mechanisms and making robust predictions regarding future consequences of shifting phenologies.

Predicting Postoperative Pain Based on Preoperative Pain Perception

Predicting Postoperative Pain Based on Preoperative Pain Perception

Comparison of the Cold Pressor Test and Contact Thermode-Delivered Cold Stimuli for the Assessment of Cold Pain Sensitivity

Sensitivity to suprathreshold cold pain stimuli constitutes an important part of comprehensive pain sensitivity testing and can be assessed by the cold pressor test or by using a contact thermode-based testing device. One major difference between the 2 methods is the size of the surface area stimulated, which is thought to affect both recruitment of endogenous pain control mechanisms and vasomotor reactions. It is therefore not clear if the 2 methods can be used interchangeably for the assessment of cold pain. Here we applied 60-second-long stimuli at approximately 3 degrees C to the hands of 47 subjects by both methods. Pain intensity ratings (on a scale from 0 to 10) were significantly higher in the cold pressor test than in the thermode cold test (6.3 +/- 1.8 vs 3.9 +/- 2), associated with a higher rate of dropouts within the 60 seconds (64 vs 11%). Nonetheless, pain intensity ratings obtained with both methods were highly correlated (r = .70). However, the thermode cold test shared a larger amount of variance with 1 or more of the other pain intensity rating tests (phasic and tonic heat, pinprick) than the cold pressor test (53% vs 30%) while the cold pressor test contained a larger proportion of unique variance (39 vs 26%). This article compares 2 methods of cold pain assessment in humans and analyzes their relationship to heat and pinprick pain. It could help researchers select the appropriate cold pain test for their study. It may also promote our understanding of commonalities and differences between different pain modalities.

Nociceptor Sensitization by Proinflammatory Cytokines And Chemokines

Cytokines are small proteins with a molecular mass lower than 30 kDa. They are produced and secreted on demand, have a short life span and only travel over short distances if not released into the blood circulation. In addition to the classical interleukins and the chemotactic chemokines, growth factors like VEGF or FGF and the colony stimulating factors are also considered cytokines since they have pleiotropic actions and regulatory function in the immune system. Despite the redundancy and pleiotropy of the cytokine network, specific actions of individual cytokines and endogenous control mechanisms have been identified. Particular local profiles of the classical proinflammatory cytokines are associated with inflammatory hypersensitivity and suggest an early involvement of TNFα, IL-1s and IL-6. An increasing number of novel cytokines and the more recently discovered chemokines are being associated with pathological pain states. Besides acting as pro- or anti-inflammatory mediators increasing evidence indicates that cytokines act on nociceptors. Neurons within the nociceptive system express neuronal receptors and specifically bind cytokines or chemokines which regulate neuronal excitability, sensitivity to external stimuli and synaptic plasticity. A first step to- wards a more mechanistic and individual pain therapeutic strategy could be avoidance of hypersensitive pain processing by either neutralization strategies for the proalgesic cytokines or by shifting the balance in favour of antialgesic members of the cytokine-chemokine network.

Long-term depression of pain-related cerebral activation in healthy man: An fMRI study

Electrical low-frequency stimulation (LFS) of cutaneous afferents reliably induces long-term depression (LTD) of nociception and pain in man. In this study LFS effects on cerebral activation were investigated by functional magnetic resonance imaging (fMRI). In 17 healthy volunteers, nociceptive fibers of right hand dorsum were electrically stimulated via a concentric electrode. Test stimulation sessions consisted of three alternating stimulation periods and rest periods. They were performed before (Pre) and after (Post) conditioning LFS (1200 stimuli, 1 Hz) or 20 min break (Control). Volunteers rated sensory and affective pain perception. Before LFS, test stimulation produced activation in bilateral primary and secondary somatosensory cortex (S1, S2), insula, anterior cingulate cortex (ACC), superior temporal cortex (STG), prefrontal cortex and right inferior parietal lobule (IPL). After LFS, exclusively right IPL was activated. Contrast between Pre and Post LFS indicated significant activity decrease in bilateral S1, S2, and ACC and right insula, IPL, and STG. Pre Control and Pre LFS were not different. Activity in Control experiments remained unchanged. Sensory and affective pain rating solely decreased after LFS. Subsequent regression analysis showed significant correlation between pain relief and increased activity after LFS in ACC, anterior insula, striatum, frontal and temporal cortex. The study revealed LTD of pain-related cerebral activation, involving sensory, affective, cognitive, and attentional processes. Positive correlation between pain relief and increased brain activation after LFS may indicate involvement of endogenous pain control mechanisms in LTD. These experiments may help to judge the potency of LTD for future chronic pain treatment.

Proteases and antiproteases in chronic neutrophilic lung disease – relevance to drug discovery

Chronic inflammatory lung diseases such as cystic fibrosis and emphysema are characterized by higher-than-normal levels of pulmonary proteases. While these enzymes play important roles such as bacterial killing, their dysregulated expression or activity can adversely impact on the inflammatory process. The existence of efficient endogenous control mechanisms that can dampen or halt this overexuberant protease activity in vivo is essential for the effective resolution of inflammatory lung disease. The function of pulmonary antiproteases is to fulfil this role. Interestingly, in addition to their antiprotease activity, protease inhibitors in the lung also often possess other intrinsic properties that contribute to microbial killing or termination of the inflammatory process. This review will outline important features of chronic inflammation that are regulated by pulmonary proteases and will describe the various mechanisms by which antiproteases attempt to counterbalance exaggerated protease-mediated inflammatory events. These proteases, antiproteases and their modifiers represent interesting targets for therapeutic intervention.

118 The Netherlands cancer plan experience

Cyclin-dependent kinase, Cdk5, is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases with no evident role in cell cycle progression. Cdk5 is present in post-mitotic and terminally differentiated neuronal/glial cells and is also known to arrest cell cycle. Also atypical is the activation of Cdk5 by binding of a non-cyclin activator protein, namely, the Cdk5 regulatory proteins Cdk5R1 (p35), truncated Cdk5R1 (p25), or Cdk5R2 (p39). Despite its ubiquitous presence in all cells and tissues, Cdk5 is often referred to as a neuron-specific kinase largely due to the abundant presence of the activator proteins in neuronal cells. Recently, this concept of a canonical neuronal function of Cdk5 has been extended, if not challenged, by the observation of p35 and p39 expression, as well as Cdk5 activity, in multiple non-neuronal cells. Extraneuronal Cdk5 regulates critical biological processes including transcript-selective translation control for regulation of macrophage gene expression, glucose-inducible insulin secretion, hematopoietic cell differentiation, vascular angiogenesis, cell migration, senescence, and wound-healing, among others. Recent advances in the extraneuronal functions of Cdk5 are reviewed and discussed here in the context of their physiological activities and pathophysiological implications with some speculative comments on the endogenous control mechanisms that might “turn on” Cdk5 activity. The potential importance of targeted inhibition of Cdk5 as therapeutic agents against glucotoxicity, diabetes, cardiovascular diseases, and cancer is also discussed.

Temporal Filtering of Nociceptive Information by Dynamic Activation of Endogenous Pain Modulatory Systems

Endogenous pain control mechanisms have long been known to produce analgesia during "flight or fight" situations and to contribute to cognitively driven pain modulation, such as placebo analgesia. Afferent nociceptive information can also directly activate supraspinal descending modulatory systems, suggesting that these mechanisms may participate in feedback loops that dynamically alter the processing of nociceptive information. The functional significance of these feedback loops, however, remains unclear. The phenomenon of offset analgesia -- disproportionately large decreases in pain ratings evoked by small decreases in stimulus intensity -- suggests that dynamic activation of endogenous pain inhibition may contribute to the temporal filtering of nociceptive information. The neural mechanisms that mediate this phenomenon remain currently unknown. Using functional magnetic resonance imaging, we show that several regions of the midbrain and brainstem are differentially activated during offset analgesia. These activations are consistent with the location of areas such as the periaqueductal gray (PAG), rostral ventral medulla, and locus ceruleus that have substantial roles in descending inhibition of pain. This transient analgesia contributes to the temporal filtering of nociceptive information by producing a perceptual amplification of the magnitude and duration of decreases in noxious stimulus intensity. Together with the involvement of PAG and associated brainstem mechanisms in cognitively generated analgesia, the present observations suggest that the fundamental role of endogenous pain modulatory mechanisms is to dynamically shape the processing of nociceptive signals to best fit with the ever-changing demands of the environment.

Excitatory and inhibitory pain mechanisms during the menstrual cycle in healthy women

Sex differences in pain perception have been clearly documented in the literature during the last decades and it has been shown that women perceived more pain than men. Sex hormones (SHs) are thought to be one of the main mechanisms which explain sex differences in pain. Pain is a dynamic phenomenon involving both excitatory and inhibitory mechanisms. Previous studies have verified the effect of SH on excitatory mechanisms but not on endogenous pain inhibitory mechanisms. The main objective of this study was to establish if pain perception and diffuse noxious inhibitory control (DNIC) vary across the menstrual cycle (MC). Thirty-two healthy women with a regular MC were tested three times across their MC (days 1–3, days 12–14 and days 19–23). Experimental pain consisted of two tonic heat pain stimulations (thermode) separated by a 2-min cold pressor test (CPT) (conditioning stimulus activating DNIC). Pain ratings were measured with a visual analogue scale. Heat pain threshold, pain tolerance and mean pain intensity during both the 2-min thermode test and CPT did not vary throughout the MC. However, we found significantly more pain inhibition (DNIC effectiveness) during the ovulatory phase compared to the menstrual and luteal phases ( p = 0.05). The main finding of this study is the observation that only inhibitory mechanisms (DNIC analgesia) and not excitatory pain mechanisms vary throughout the MC, where women have greater DNIC in the ovulatory phase. The higher occurrence of pain and lower pain threshold previously reported during the MC could be related to a reduction in endogenous pain control mechanisms.

Strategies to optimize two-dimensional gel electrophoresis analysis of the human joint proteome

Due to the complex structure of the articular joint, it requires great effort to fully understand joint disease pathogenesis. The proteomic analysis of articular joint tissues could contribute greatly to our insight into the endogenous control mechanisms of matrix turnover and the unravelling of the molecular and cellular mechanisms involved in the progression of the arthritides. To date, most proteome analysis strategies use the two-dimensional gel electrophoresis (2-DE) technique to separate proteins according to their isoelectric point, molecular mass, solubility and relative abundance. In this work, we describe optimization of human joint sample preparation techniques to obtain high quality 2-DE maps of human joint tissues (cartilage and synovium), cells (chondrocytes and synoviocytes) and synovial fluid. These techniques improve the performance of gel-based differential proteomic analysis, and facilitate the application of proteomics to rheumatology studies.

DNIC's efficacy across de menstrual cycle in women with fibromyalgia

Fibromyalgia syndrome (FMS) is a widespread disorder of unknown aetiology affecting 2-4% of the general population in which women are about nine times more likely to develop fibromyalgia than men.1 Nonetheless, several hypotheses have been advanced to explain the onset of symptoms. One of these supports a reduction of diffuse noxious inhibitory controls (DNIC) in fibromyalgics.2 Another hypothesis comes from the fact that the higher prevalence of FMS in women should be related to sex hormones (SH). The goal of this study was to examine DNIC's efficiency in relation to the menstrual cycle of women with FMS. We measured DNIC recruitment and blood level of testosterone (T), estrogens (E) and progesterone (P) at three phases (lutheal, ovulation and menstrual) of a regular menstrual cycle in women with FMS. DNIC were activated by the persistent pain stimulation (PPS) procedure, which consists in a continuous nociceptive heat stimulation using a constant temperature thermode for two minutes (at the forearm) producing temporal summation of pain.3 DNIC activity was then indexed by comparing temporal summation effects recorded before and after a two minutes immersion of the contralateral arm in cold water (12°C). FMS patients reported similar pain ratings before and after the immersion procedure in menstrual (low E and P) and ovulation phases (high E, low P). However, they reported less pain after the immersion procedure during the lutheal phase (low E, high P). This pain diminution showed the analgesic effect caused by the activation of the DNIC. Moreover, SH analysis showed that FMS patients have normal levels of T, E and P. These results suggest that endogenous pain control mechanisms in FM female patients are modulated by menstrual cycle. (1. Wolfe, J Musculoskelet Pain, 1993; 2. Julien, Pain, 2005; 3. Tousignant-Laflamme, Brain Research, 2008.) Fibromyalgia syndrome (FMS) is a widespread disorder of unknown aetiology affecting 2-4% of the general population in which women are about nine times more likely to develop fibromyalgia than men.1 Nonetheless, several hypotheses have been advanced to explain the onset of symptoms. One of these supports a reduction of diffuse noxious inhibitory controls (DNIC) in fibromyalgics.2 Another hypothesis comes from the fact that the higher prevalence of FMS in women should be related to sex hormones (SH). The goal of this study was to examine DNIC's efficiency in relation to the menstrual cycle of women with FMS. We measured DNIC recruitment and blood level of testosterone (T), estrogens (E) and progesterone (P) at three phases (lutheal, ovulation and menstrual) of a regular menstrual cycle in women with FMS. DNIC were activated by the persistent pain stimulation (PPS) procedure, which consists in a continuous nociceptive heat stimulation using a constant temperature thermode for two minutes (at the forearm) producing temporal summation of pain.3 DNIC activity was then indexed by comparing temporal summation effects recorded before and after a two minutes immersion of the contralateral arm in cold water (12°C). FMS patients reported similar pain ratings before and after the immersion procedure in menstrual (low E and P) and ovulation phases (high E, low P). However, they reported less pain after the immersion procedure during the lutheal phase (low E, high P). This pain diminution showed the analgesic effect caused by the activation of the DNIC. Moreover, SH analysis showed that FMS patients have normal levels of T, E and P. These results suggest that endogenous pain control mechanisms in FM female patients are modulated by menstrual cycle. (1. Wolfe, J Musculoskelet Pain, 1993; 2. Julien, Pain, 2005; 3. Tousignant-Laflamme, Brain Research, 2008.)

Physiology of the endothelium: from a molecular point of view

The endothelium plays a crucial role in the prevention of vascular inflammation and the events leading to atherosclerosis mainly by the generation of anti-inflammatory autacoids. The most important endothelium-derived autacoid is the vasodilator nitric oxide (NO) which influences the expression of several vascular genes in addition to its acute effects on vessel tone. One particularly interesting example of the effect of NO on signalling is its role in the shear stress-induced activation of the AMP-activated protein kinase (AMPK). This NO-activated kinase phosphorylates and inactivates the HMG CoA reductase in endothelial cells, thus decreasing the activity of small G proteins such as Ras and the subsequent ERK kinases. Loss of this endogenous control mechanism during endothelial dysfunction (which is associated with a decrease in endothelium-derived NO) contributes to endothelial cell activation.