Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.
Atherosclerosis 2001 Apr
PMID:Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice. 1125 98

PgPepO is a homologue of endothelin-converting enzyme-1 (ECE-1), with which it shares 31% identity. PgPepO was isolated from the periodontal pathogen Porphyromonas gingivalis. Recent studies have suggested a link between periodontal and cardiovascular disease, and several groups have suggested that bacterial and viral infections may contribute to the latter. P. gingivalis possesses the ability to invade, and multiply within, aortic endothelial cells and has been localized to atherosclerotic plaques. PgPepO was expressed and purified to homogeneity and we have begun detailed functional analysis, in terms of substrate preference and inhibitor specificity, in order to provide active-site comparisons with other members of the neprilysin (NEP)/ECE family. PgPepO possesses similar substrate specificity to ECE-1 and has been shown to cleave big endothelin-1 (big ET-1), big ET-2 and big ET-3, converting the substrates into their respective mature endothelin peptides. Substance P, angiotensin I, angiotensin II and neurotensin are all cleaved at multiple sites by PgPepO and the kinetics of these reactions have been compared. The potent vasoconstrictor urotensin II is not hydrolysed by PgPepO. Cleavage of bradykinin by PgPepO occurs at the Pro(7)-Phe(8) bond and is inhibited by the NEP and ECE-1 inhibitor phosphoramidon in a pH-dependent fashion (IC(50) =10 microM at pH 7.0) but not by thiorphan, an NEP-specific inhibitor. PgPepO activity is completely inhibited by EDTA. Characterization of this enzyme is important in elucidating possible links between periodontal pathogens and cardiovascular disorders such as atherosclerosis, and provides an opportunity to gain structural information on a bacterial protein with striking similarity to human ECE-1.
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PMID:Characterization of PgPepO, a bacterial homologue of endothelin-converting enzyme-1. 1219 62

Diffuse intimal thickening (DIT) that develops as a physiologic adaptation in the arterial wall has been implicated to have a predilection for atherosclerosis. We histologically investigated the lipid accumulation process in the human coronary DIT by focusing on the localization of normal and oxidized low-density lipoproteins (LDLs). Immunohistochemistry for apolipoprotein B 100 (a major apolipoprotein of LDL) and 8-iso-prostaglandin F(2alpha) (an oxidative product in LDL) showed substantial accumulation of oxidized relative to normal LDLs in the deep layers of DIT (52/139 segments). Subendothelial deposition of normal rather than oxidized LDLs, known as an early event of fatty streak formation, was less frequently found (13/139 segments). In contrast with fibrofatty lesions, lipid accumulation localized deep in DIT was characterized by fine lipid droplets scattered in the preserved tissue and by its association with neither macrophage accumulation nor apoptosis in the constituent cells. On the other hand, the deep intimal location of lipid accumulation clearly coincided with increased type I and type III collagen and elastic fibers but rarely with sulfated proteoglycans including decorin, which were all strongly expressed in advanced lesions. This lipid accumulation was found only in sites with DIT of more than 200 micro m, occasionally extending to the inner media and involving neovessel formation around it. The presence of deep intimal lipid accumulation was associated with reduced endothelium-dependent relaxation to substance P in isolated coronary rings. These results suggest that normal and oxidized LDLs accumulate preferably in the nutritional border zone of established DIT involving local extracellular matrix alterations but independently of inflammatory or apoptotic processes. This may contribute to the functional and morphologic abnormalities seen in human coronary atherogenesis that progresses slowly with age.
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PMID:Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. 1237 78

The subject of neuroinflammation is reviewed. In response to psychological stress or certain physical stressors, an inflammatory process may occur by release of neuropeptides, especially Substance P (SP), or other inflammatory mediators, from sensory nerves and the activation of mast cells or other inflammatory cells. Central neuropeptides, particularly corticosteroid releasing factor (CRF), and perhaps SP as well, initiate a systemic stress response by activation of neuroendocrinological pathways such as the sympathetic nervous system, hypothalamic pituitary axis, and the renin angiotensin system, with the release of the stress hormones (i.e., catecholamines, corticosteroids, growth hormone, glucagons, and renin). These, together with cytokines induced by stress, initiate the acute phase response (APR) and the induction of acute phase proteins, essential mediators of inflammation. Central nervous system norepinephrine may also induce the APR perhaps by macrophage activation and cytokine release. The increase in lipids with stress may also be a factor in macrophage activation, as may lipopolysaccharide which, I postulate, induces cytokines from hepatic Kupffer cells, subsequent to an enhanced absorption from the gastrointestinal tract during psychologic stress. The brain may initiate or inhibit the inflammatory process. The inflammatory response is contained within the psychological stress response which evolved later. Moreover, the same neuropeptides (i.e., CRF and possibly SP as well) mediate both stress and inflammation. Cytokines evoked by either a stress or inflammatory response may utilize similar somatosensory pathways to signal the brain. Other instances whereby stress may induce inflammatory changes are reviewed. I postulate that repeated episodes of acute or chronic psychogenic stress may produce chronic inflammatory changes which may result in atherosclerosis in the arteries or chronic inflammatory changes in other organs as well.
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PMID:Stress and the inflammatory response: a review of neurogenic inflammation. 1248 Apr 95

This review summarizes some basic properties and distribution of angiotensin I converting enzyme (ACE). ACE is one of several biologically important ectoproteins that exists in both membrane-bound and soluble forms. Localized on the surface of various cells, ACE is inserted at the cell membrane via its carboxyl terminus. Human plasma ACE originates from endothelial cells while other body fluids may contain ACE that originates from epithelial, endothelial or germinal cells. The two isoforms of ACE, the two-domain somatic form and the single domain germinal form, convert angiotensin I to angiotensin II, and metabolize kinins and many other biologically active peptides, including substance P, chemotactic peptide and opioid peptides. The broad spectrum of substrates for ACE and its wide distribution throughout the body indicates that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in additional physiologic processes such as neovascularization, fertilization, atherosclerosis, kidney and lung fibrosis, myocardial hypertrophy, inflammation and wound healing. Future research should explore the possible functions of tissue ACE and its systemic role as a pressor agent. ACE inhibitors have achieved widespread use in the treatment of hypertension and the protection of end-organ damage in cardiovascular and renal diseases. Potential problems related to side effects and compliance of such therapy need to be addressed. A safer way of producing therapeutic effects is promised by the delivery of the ACE antisense sequences by a vector producing a permanent inhibition of ACE and long-term control of blood pressure in hypertensive patients.
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PMID:Properties and distribution of angiotensin I converting enzyme. 1257 Jul 87

In the adventitia of large arteries, dendritic cells are located between nerve fibers, some of which contain substance P. The aim of the present study was to examine whether neurokinin 1 receptor (NK-1R) was expressed by dendritic cells in the arterial wall. Parallel sections of aortic and carotid artery segments were immunostained with anti-NK-1R and cell-type-specific antibodies. Dendritic cells in the arterial wall expressed NK-1R, albeit at a low level. Other cells, which intensely expressed NK-1R, were located along the border between the media and adventitia. They did not co-express any dendritic cell markers, including fascin, CD1a, S100, or Lag-antigen, and were negative for CD68, CD3, and mast cell tryptase. These NK-1R(+) cells were laser-capture microdissected and studied by means of electron-microscopic analysis. The microdissected cells were in direct contact with nerve endings, and their ultrastructure was typical of the interstitial cells of Cajal present in the gastrointestinal tract. Further systematic electron-microscopic analysis revealed that the cells displaying the features typical of interstitial cells of Cajal were a basic element of the human arterial wall architectonics. Arterial interstitial cells of Cajal were negative for c-kit but they expressed vasoactive intestinal peptide receptor 1 (VIPR1). Destructive alterations of contacts between arterial interstitial cells of Cajal and nerve endings were observed in arterial segments with atherosclerotic lesions. The functional significance of the arterial interstitial cells of Cajal and their possible involvement in atherosclerosis and other vascular diseases need clarification.
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PMID:Subset of cells immunopositive for neurokinin-1 receptor identified as arterial interstitial cells of Cajal in human large arteries. 1590 5

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.
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PMID:Cytokine dysregulation, inflammation and well-being. 1616 5

Atherosclerotic vascular disease is associated with abnormal vasomotor function and oxidized low density lipoproteins (OxLDL) are believed to play a keyrole therein. Several compounds emerging from LDL lipid peroxidation have been shown to be able to alter vasomotion but the role of oxidized apoB in this process is not fully understood. Myeloperoxidase has been identified in atherosclerotic lesions and hypochlorite produced by this enzyme represents a strong oxidant. LDL oxidation by hypochlorite differs from most other forms of LDL oxidation in that hypochlorite-mediated oxidation shows a predilection for the protein moiety of LDL and does not result in lipid peroxidation. In this work, we use porcine coronary artery segments and show that hypochlorite-oxidized LDL (hyp-OxLDL) are able to impair dilatation induced by substance P in a dose- and modification-dependent way. Treatment of hyp-OxLDL with methionine resulted in quantitative elimination of reactive chloramines in LDL and complete recovery of relaxation. As application of the scavenger receptor antagonist maleylated albumin strongly interferes with the effects of hyp-OxLDL on vasomotion, we conclude that specific binding of hypochlorite-modified apoB is likely to be involved in mediating the observed effects.
Atherosclerosis 2007 Feb
PMID:Redox-sensitive impairment of porcine coronary artery vasodilation by hypochlorite-modified LDL. 1673 Jul 31

Associations between stress and health outcomes have now been carefully documented, but the mechanisms by which stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major stress hormones, inhibit systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the stress system, through induction of a Th2 shift may protect the organism from systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive stress system, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which stress affects disease susceptibility, activity, and outcome of various immune-related diseases.
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PMID:Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. 1685 35

Vascular-related diseases, including Blackfoot Disease and atherosclerosis, are prominent clinical findings among populations residing in arseniasis areas. While oxidative stress provided a general but nonspecific mechanistic base for arsenic-induced endothelial cell damage in vitro, more specific mechanism is needed to explain the highly targeted vascular lesions induced by arsenic in vivo. Based on our previous studies, we hypothesized that arsenic exerted its action on blood vessels via the neurogenic inflammation process involving release of a neuropeptide (substance P) and activation of endothelial Neurokinin 1 (NK-1) receptor in vivo. Indeed, our present study demonstrated a significantly higher substance P levels in arsenic-treated tissues when compared to saline-treated controls indicating a rapid release of substance P under the influence of arsenic. Furthermore, the arsenic-induced vascular leakage could be significantly reduced when the neurogenic inflammation process was interrupted (via either disruption on the release of substance P, interference on the action of substance P, or blockage of endothelial NK-1 receptor) showing that the neurogenic inflammation process was indeed involved. Histamine release was not found to play a significant role in arsenic-induced vascular permeability change. Our present study affirmed a de novo concept that a pathophysiological mechanism involving the neurogenic release of substance P and activation of endothelial NK-1 receptor underlies the arsenic-induced vascular injury and dysfunction in vivo. This pathophysiological process constituted a two-tiered biological interaction between the nervous system and vascular system and therefore was not readily unveiled by traditional in vitro studies in the past. Our present finding unveiled an important de novo concept on arsenic vascular toxicity in vivo.
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PMID:Involvement of substance P and neurogenic inflammation in arsenic-induced early vascular dysfunction. 1705 41


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