Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of fibrosis in the chronically hypertensive heart is associated with infiltration of inflammatory cells and cardiac hypertrophy. In this study, an inhibitor of the proinflammatory enzyme, group IIA human secretory phospholipase A2 (sPLA2-IIA), has been found to prevent collagen deposition as an important component of cardiovascular remodeling in a rat model of developing chronic hypertension. Daily treatment of young male spontaneously hypertensive rats (SHR) with an sPLA2-IIA inhibitor (KH064, 5-(4-benzyloxyphenyl)-4S-(phenyl-heptanoylamino)-pentanoic acid, 5 mg/kg/day p.o.) prevented increases in the content of perivascular (SHR 20.6 +/- 0.9%, n = 5; SHR+KH064 14.0 +/- 1.2%, n = 5) and interstitial (SHR 7.9 +/- 0.3%, n = 6; SHR+KH064 5.4 +/- 0.7%, n = 6) collagen in the left ventricle of rat hearts, but did not affect numbers of infiltrating monocytes/macrophages, left ventricular hypertrophy (SHR 2.88 +/- 0.08, n = 12; SHR+KH064 3.09 +/- 0.08 mg/g body weight, n = 9), increased systolic blood pressure, or thoracic aortic responses. This selective antifibrotic activity suggests that sPLA2-IIA may have an important but specific role in cardiac fibrosis, and that its inhibitors could be useful in dissecting molecular pathways leading to fibrotic conditions.
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PMID:Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats. 1670 61

Rgs2 (regulator of G-protein signaling-2)-deficient mice exhibit severe hypertension, and genetic variations of RGS2 occur in hypertensive patients. RGS2 mRNA up-regulation by angiotensin II (Ang II) in vascular smooth muscle cells (VSMC) is a potentially important negative feedback mechanism in blood pressure homeostasis, but how it occurs is unknown. Here we demonstrate that group VIA phospholipase A2 (iPLA2beta) plays a pivotal role in Ang II-induced RGS2 mRNA up-regulation in VSMC by three independent approaches, including pharmacologic inhibition with a bromoenol lactone suicide substrate, suppression of iPLA2beta expression with antisense oligonucleotides, and genetic deletion in iPLA2beta-null mice. Selective inhibition of iPLA2beta by each of these approaches abolishes Ang II-induced RGS2 mRNA up-regulation. Furthermore, using adenovirus-mediated gene transfer, we demonstrate that restoration of iPLA2beta-expression in iPLA2beta-null VSMC reconstitutes the ability of Ang II to up-regulate RGS2 mRNA expression. In contrast, Ang II-induced vasodilator-stimulated phosphoprotein phosphorylation and Ang II receptor expression are unaffected. Moreover, in wild-type but not iPLA2beta-null VSMC, Ang II stimulates iPLA2 enzymatic activity significantly. Both arachidonic acid and lysophosphatidylcholine, products of iPLA2beta action, induce RGS2 mRNA up-regulation. Inhibition of lipoxygenases, particularly 15-lipoxygenase, and cyclooxygenases, but not cytochrome P450-dependent epoxygenases inhibits Ang II- or AA-induced RGS2 mRNA expression. Moreover, RGS2 protein expression is also up-regulated by Ang II, and this is attenuated by bromoenol lactone. Disruption of the Ang II/iPLA2beta/RGS2 feedback pathway in iPLA2beta-null cells potentiates Ang II-induced vasodilator-stimulated phosphoprotein and Akt phosphorylation in a time-dependent manner. Collectively, our results demonstrate that iPLA2beta participates in Ang II-induced transcriptional up-regulation of RGS2 in VSMC.
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PMID:Group VIA phospholipase A2 (iPLA2beta) participates in angiotensin II-induced transcriptional up-regulation of regulator of g-protein signaling-2 in vascular smooth muscle cells. 1761 34

Few studies have investigated the role of elevated lipoprotein-associated phospholipase A2 (Lp-PLA(2)) with stroke risk, and those that have are based on small numbers of strokes. No study has evaluated the effect of hormone therapy use on the association of Lp-PLA(2) and stroke. We assessed the relationship between Lp-PLA(2) and the risk of incident ischemic stroke in 929 stroke patients and 935 control subjects in the Hormones and Biomarkers Predicting Stroke Study, a nested case-control study from the Women's Health Initiative Observational Study. Mean (SD) levels of Lp-PLA(2) were significantly higher among case subjects (309.0 [97.1]) than control subjects (296.3 [87.3]; P<0.01). Odds ratio for ischemic stroke for the highest quartile of Lp-PLA(2), compared with lowest, controlling for multiple covariates, was 1.08 (95% CI: 0.75 to 1.55). However, among 1137 nonusers of hormone therapy at baseline, the corresponding odds ratio was 1.55 (95% CI: 1.05 to 2.28),whereas there was no significant association among 737 hormone users (odds ratio: 0.70; 95% CI: 0.42 to 1.17; P for interaction=0.055). Moreover, among nonhormone users, women with high C-reactive protein and high Lp-PLA2 had more than twice the risk of stroke (odds ratio: 2.26; 95% CI: 1.55 to 3.35) compared with women low levels in both biomarkers. Furthermore, different stroke cases were identified as high risk by Lp-PLA(2) rather than by C-reactive protein. Lp-PLA(2) was associated with incident ischemic stroke independently of C-reactive protein and traditional cardiovascular risk factors among nonusers of hormone therapy with highest risk in those who had both high C-reactive protein and high Lp-PLA(2).
Hypertension 2008 Apr
PMID:Lipoprotein-associated phospholipase A2, hormone use, and the risk of ischemic stroke in postmenopausal women. 1825 35

Pancreatic phospholipase A2 (phospholipase A2 group 1B, G1B) belongs to the superfamily of secreted phospholipase A2 (PLA2) enzymes. G1B has been proposed to be a potential target for diseases such as hypertension, obesity, and diabetes. Human pancreatic prophospholipase A2 (pro-hG1B) is activated by cleavage of the first seven-residue propeptide (phospholipase A2 propeptide, PROP). However, questions still remain on the mode of action for pro-hG1B. In this work, we expressed pro-hG1B in Pichia pastoris and determined the crystal structure at 1.55-A resolution. The x-ray structure demonstrates that pro-hG1B forms a trimer. In addition, PROP occupies the catalytic cavity and can be self-cleaved at 37 degrees C. A new membrane-bound surface and activation mechanism are proposed based on the trimeric model of pro-hG1B. We also propose a new autoproteolytic mechanism for pro-hG1B by the reaction triad Asp49-Arg0-Ser(-2) that is similar to the serine protease catalytic triad.
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PMID:Structural insight into the activation mechanism of human pancreatic prophospholipase A2. 1929 24

This study investigated the correlation of sPLA2 (secretory phospholipase A2) activity with the atheromatosis extent in subjects with coronary artery disease (CAD) undergoing coronary angiography. We analyzed 123 patients, including 35 subjects with angiographically normal coronary arteries (controls), 31 with mild/moderate atheromatosis (stenosis of 30-70% of the luminal diameter in one or more coronary arteries) and 57 with severe atheromatosis (>70% stenosis). Plasma sPLA2 activity was significantly higher in subjects with severe [127.7 U/ml (102.3-162.7); p < 0.0001] and mild/moderate [112.0 U/ml (100.6-146.9); p < 0.0001] atheromatosis than in controls [19.8 U/ml (15.1-32.1)]. In a multiple logistic regression model, adjusted for age, gender, body mass index, tabagism, hypertension, sedentarism, family history for coronary artery disease, diabetes mellitus, total cholesterol, HDLc, LDLc, triglycerides, high sensitivity C-reactive protein and phospholipase A2, only sPLA2 was observed to be independently associated with severe CAD (>70% of stenosis) (p < 0.0001).
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PMID:Secretory phospholipase A2 in patients with coronary artery disease. 1944 49

To combat cardiovascular disease (CVD), physicians and allied health care professionals often focus on modifying conventional risk factors such as cigarette smoking, hypertension, hypercholesterolemia, and diabetes. However, a recent review of published research demonstrated that 75% to 90% of coronary artery disease (CAD) incidence is explained by these risk factors, either alone or in combination. This has stimulated a vigorous search for other correctable risk factors (ie, to explain the remaining incidence [10%-25%]), including genetic anomalies, markers of inflammation (C-reactive protein, lipoprotein-associated phospholipase A2), and specific lipid/lipoprotein particles to enhance risk stratification. Nevertheless, an escalating body of research provides strong evidence for the adverse effects of psychosocial factors in the development of CVD and in the prognosis of patients with CAD.
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PMID:Impact of psychosocial risk factors on the heart: changing paradigms and perceptions. 2004 26

Acute respiratory distress syndrome (ARDS) is the most devastating form of acute lung injury (ALI) or pulmonary edema (PE). We presented the experimental studies and clinical investigations of two serious forms of ALI. Drastic and severe PE could be induced by intracranial hypertension or cerebral compression (CC). The CC-induced PE was attributed to overactivation of the medullary sympathetic mechanism. Sympathetic vasoconstriction of the systemic and pulmonary resistance and capacitance vessels caused shift of blood volume from the splanchnic vascular beds to the lung. The hemodynamic changes led to systemic and pulmonary hypertension. Consequently, left ventricular failure as evidenced by dramatic decline in aortic flow with a slow decrease in pulmonary flow resulted in pressure and volume loading in the pulmonary circulation. These changes finally produced severe alveolar flooding and sudden death. Vasodilators such as sodium nitroprusside or nitroglycerin were capable of reducing the CC-induced pulmonary pathology and hemodynamic alterations. Fat embolism syndrome (FES) is a serious clinical problem in patients suffering from long bone fractures. ARDS may develop and cause mortality. Our laboratory reported a total of 14 subjects associated with FES and died of ARDS. We also developed a simple technique to produce FES. Corn oil was mixed with distilled water to form fatty micelles. Intravenous administration of or introduction of fatty micelles in anesthetized rats or isolated perfused lungs caused severe alveolar damage. Our clinical observation and animal experimentation revealed that infusion of fatty acids caused physical phase, resulting in microvascular obstruction accompanied by pulmonary hypertension and increased capillary permeability. Thereafter, the lipases in the lung hydrolyzed the neutral fat and released free fatty acids and biochemical mediators which were toxic to the lung. Our data have suggested that nitric oxide (NO), inducible NO synthase (iNOS), phospholipase A2, free radical and inflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta and interleukin-6) are involved in the biochemical phase of FES with ARDS. The alveolar macrophages are the major source of iNOS. Later study also found that neutrophil elastase and myeloperoxidase were elevated following fat embolism. N-acetylcysteine (an antioxidant), and NOS inhibitors such as Nomega nitro-L-arginine methyl ester (L-NAME), S-methylisothiourea (SMT) or L-N6 (1-iminoethyl)-lysine (L-Nil) were able to abrogate the FES or the fat embolism-induced changes.
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PMID:From neurogenic pulmonary edema to fat embolism syndrome: a brief review of experimental and clinical investigations of acute lung injury and acute respiratory distress syndrome. 2035 24

The neuroendocrine theory of aging identified a cluster of conditions (hypertension, obesity, dyslipidemia, diabetes type 2, menopause, late onset depression, vascular cognitive impairment, impairment of immune defense, and some forms of cancer, e.g., breast and prostate) as age-associated neuroendocrine disorders (AAND). Obesity, dyslipidemia, hypertension, and type 2 diabetes were later described as metabolic syndromes (MetS). Chronic inflammation is currently considered as a common feature of MetS/AAND. One of the mechanisms by which chronic inflammation might trigger and/or maintain the development of MetS/AAND is transcriptional induction of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of tryptophan (TRY)-kynurenine (KYN) pathway, by pro-inflammatory cytokines (PIC). Activation of IDO shifts TRY metabolism from serotonin synthesis to formation of "kynurenines." Diminished serotonin production is associated with mental depression while increased formation of kynurenines might contribute to development of MetS/AAND via their apoptotic, neurotoxic, and pro-oxidative effects, and upregulation of inducible nitric oxide synthase, phospholipase A2, arachidonic acid, prostaglandin, 5-lipoxygenase, and leukotriene cascade. The combined presence of high producers of alleles of polymorphic PIC genes (e.g., interferon-gamma and tumor necrosis factor alpha) might account for the genetic predisposition to high levels of PIC production, leading to "superinduction" of IDO. The other rate-limiting enzyme of the TRY-KYN pathway, TRY 2,3-dioxygenase, is activated by substrate (TRY) and cortisol. Therefore, KYN-TRY metabolism might be the meeting point for gene-environment interaction and a new target for prevention and treatment of MetS/AAND.
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PMID:Metabolic syndrome, age-associated neuroendocrine disorders, and dysregulation of tryptophan-kynurenine metabolism. 2063 4

Predictive models for future risk of coronary heart disease (CHD) based on traditional risk factors, such as age, male gender, LDL cholesterol, HDL cholesterol, diabetes mellitus, hypertension, smoking and family history of premature CHD, are quite robust but leave room for further improvement. Thus, efforts are being made to assess additional biomarkers for CHD, such as, lipoprotein (a), C-reactive protein, fibrinogen, lipoprotein-associated phospholipase A2, homocysteine and others. However, none of the novel biomarkers has demonstrated improved prediction beyond traditional risk factor models in a consistent fashion across multiple cohorts. Many criteria have to be fulfilled before a biomarker can be considered clinically relevant. Another way is to develop new models predicting long-term or life-time risk of CHD. Further research using novel biomarkers and long-term predictive models has the potential to improve CHD risk prediction.
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PMID:What is the role of alternative biomarkers for coronary heart disease? 2152 14

Thorough control of risk factors is pivotal for cardiocerebrovascular diseases. As classic risk assessment accounts for only 50% of risk variability and due to the role of inflammatory processes in endothelial dysfunction and atherosclerotic plaque rupture, it is necessary to identify new biomarkers for risk prediction. In addition to the inflammatory marker high sensibility C-reactive protein (hs-CRP), lipoprotein associated phospholipase A2 (Lp-PLA2) is gaining increasing significance, since it is directly involved in the pathogenesis of atherosclerotic plaque progression. Lp-PLA2 is highly specific for vascular inflammation, has low biological variability, and plays a causative role in atherosclerotic plaque inflammation. It belongs to the group of intracellular and secretory phospholipase enzymes that can hydrolyze sn-2 phospholipid ester bond of cellular membranes and lipoproteins. Lp-PLA2 enzyme is formed by macrophages and foam cells in atherosclerotic plaque, and is associated primarily with LDL particles in blood. Lp-PLA2 that is bound to LDL is the sole enzyme responsible for hydrolysis of oxidized phospholipids (oxPL) on LDL particles. Lp-PLA2 hydrolyzes oxPL at the surface of lipoproteins, but has weak activity against non-oxPL. Lp-PLA2 is also the enzyme that hydrolyzes oxPL on HDL particles, where it may have a role in the antioxidative function of HDL. The distribution of Lp-PLA2 between LDL and HDL particles depends on the extent of Lp-PLA2 glycosylation, which may affect the activity of Lp-PLA2 in plasma. Stable atherosclerotic plaques contain few inflammatory cells and a small amount of Lp-PLA2. In contrast, unstable plaques most often do not have significant impact on arterial lumen but may be detected by its thin connective tissue cap, low collagen and high lipid content. A distinguishing factor between stable and unstable atherosclerotic plaque may also be the presence of activated inflammatory cells and increased Lp-PLA2 concentration in unstable plaque. These new insights indicate that Lp-PLA2 may be a risk factor, which is important for the formation of atherosclerotic plaque but also for its rupture. The purpose of applying markers of inflammation is to improve stratification of patients at risk, so that treatment intensity may be adjusted to the risk level. Lp-PLA2 inhibition is associated with decreased cytokines. Lipid-affecting drugs stabilize atherosclerotic plaque by reducing the central lipid core, decreasing macrophage infiltration, and thickening of the connective tissue cap. These drugs reduce Lp-PLA2 concentration and the frequency of cardiocerebrovascular events as well. Besides acting as a specific marker of atherosclerotic plaque inflammation, Lp-PLA2 has a significant prognostic value because of its direct role in the formation of rupture-prone atherosclerotic plaque, unlike classic risk factors, for example lipid measurement or vascular imaging, which do not directly estimate acute ischemic potential in the arterial wall. Studies have demonstrated correlation between increased Lp-PLA2 concentrations and enhanced risk of cardiocerebrovascular events, even after multivariate adjustment to classic risk factors. In addition to its high specificity for vascular inflammation, Lp-PLA2 concentration is stable in terms of time, unlike, for instance, CRP levels. Lp-PLA2 has been confirmed as an independent risk predictor, which is complementary to hsCRP. It could be used in clinical practice for improved risk assessment in patients with transient cardiocerebrovascular risk, particularly in those with metabolic syndrome (obese patients with mixed dyslipidemia, hyperglycemia, insulin resistance, and arterial hypertension). Lp-PLA2 levels allow for further risk stratification of high-risk patients into a very high risk group where more aggressive therapy is recommended, as well as the achievement of LDL-cholesterol levels < 2.5 or, even better, < 2.0 mmol/L as a feasible therapeutic target. Similar to hsCRP, the levels of Lp-PLA2 are reduced by lipid-affecting drugs, while its low concentrations are associated with a very low risk of cardiocerebrovascular events both in low- and high-risk population. According to recent American guidelines for assessing the risk of cardiovascular disease, Lp-PLA2 determination is recommended as an additional marker to the classic risk assessment in patients with moderate and high risk.
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PMID:[Does Lp-PLA2 determination help predict atherosclerosis and cardiocerebrovascular disease?]. 2168 6


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