Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since little is known about the effects of reconstituted high-density lipoprotein (rHDL) in left ventricular (LV) remodeling, these effects were examined in rats after acute myocardial infraction (MI). Sixteen male Wistar rats were randomly divided into three groups: Sham-operated (n=6), and MI rats that received a permanent ligation around the proximal left coronary artery and infusions of placebo (MI group, n=5) or rHDL (containing as apolipoproteinA-I 6mg/kg) administered intravenously (MI+rHDL group, n=5). rHDL was infused once a week for 4 weeks. In addition, in vitro assays were performed to examine the effect of rHDL. The MI+rHDL group showed a significant increase in LV ejection fraction (EF) between weeks 1 and 4, a decrease in LV end-systolic diameter, compared with the progressive deterioration of LV size and function in the MI group. In addition, the MI+rHDL group showed a significant decrease in fibrotic area of MI in LV compared to that in the MI group, while there were no significant increases in capillary density or cell size in LV in the MI+rHDL group. Interestingly, the MI+rHDL group showed a significant activation of retinoblastoma and ERK (extracellular-signal-regulated kinase) but not cleaved caspase-3, p38 MAPK or Jun N-terminal kinase. rHDL suppressed H(2)O(2)-induced arrest of cell growth in myocytes. This effect was blocked by PD98059, an ERK inhibitor. In conclusions, rHDL-promoted cell survival has beneficial morphological effects that help to prevent LV remodeling and improve function after MI, and may prevent arrest of cell growth through ERK pathway in myocytes.
Atherosclerosis 2009 Mar
PMID:Reconstituted high-density lipoprotein attenuates postinfarction left ventricular remodeling in rats. 1860 12

Advanced age is a major risk factor for atherosclerosis, but how aging per se influences pathogenesis is not clear. Insulin-like growth factor-1 receptor (IGF-1R) promotes aortic vascular smooth muscle cell (VSMC) growth, migration, and extracellular matrix formation, but how IGF-1R signaling changes with age in VSMC is not known. We previously found age-related differences in the activation of Akt/FOXO3a and ERK1/2 pathways in VSMC, but the upstream signaling remains unclear. Using explanted VSMC from Fischer 344/Brown Norway F1 hybrid rats shown to display age-related vascular pathology similar to humans, we compared IGF-1R expression in early passages of VSMC and found a constitutive activation of IGF-1R in VSMC from old compared to young rats, including IGF-1R expression and its tyrosine kinase activity. The link between IGF-1R activation and the Akt/FOXO3a and ERK pathways was confirmed through the induction of IGF-1R with IGF-1 in young cells and attenuation of IGF-1R with an inhibitor in old cells. The effects of three kinase inhibitors: AG1024, LY294002, and TCN, were compared in VSMC from old rats to differentiate IGF-1R from other upstream signaling that could also regulate the Akt/FOXO and ERK pathways. Genes for p27kip-1, catalase and MnSOD, which play important roles in the control of cell cycle arrest and stress resistance, were found to be FOXO3a-targets based on FOXO3a-siRNA treatment. Furthermore, IGF-1R signaling modulated these genes through activation of the Akt/FOXO3a pathway. Therefore, activation of IGF-1R signaling influences VSMC function in old rats and may contribute to the increased risk for atherosclerosis.
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PMID:Age-related differences in insulin-like growth factor-1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells. 1861 85

Medial-to-intimal migration of SMCs is critical to atherosclerotic plaque formation and remodeling of injured arteries. Considerable amounts of the shed soluble form of the LDL receptor relative LR11 (sLR11) produced by intimal SMCs enhance SMC migration in vitro via upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. Here, we show that circulating sLR11 is a novel marker of carotid intima-media thickness (IMT) and that targeted disruption of the LR11 gene greatly reduces intimal thickening of arteries through attenuation of Ang II-induced migration of SMCs. Serum concentrations of sLR11 were positively correlated with IMT in dyslipidemic subjects, and multivariable regression analysis suggested sLR11 levels as an index of IMT, independent of classical atherosclerosis risk factors. In Lr11-/- mice, femoral artery intimal thickness after cuff placement was decreased, and Ang II-stimulated migration and attachment of SMCs from these mice were largely abolished. In isolated murine SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase/ERK/Rac1 accompanied by complex formation between uPAR and integrin alphavbeta3, a process accelerated by Ang II. Overproduction of sLR11 decreased the sensitivity of Ang II-induced activation pathways to inhibition by an Ang II type 1 receptor blocker in mice. Thus, we demonstrate a requirement for sLR11 in Ang II-induced SMC migration and propose what we believe is a novel role for sLR11 as a biomarker of carotid IMT.
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PMID:Ang II-stimulated migration of vascular smooth muscle cells is dependent on LR11 in mice. 1861 22

The nuclear receptor PPARgamma is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPARgamma activity by TNF-alpha is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPARgamma activity is regulated by TNF-alpha at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPARgamma. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPARgamma. IKK acts through at least two mechanisms: inhibition of PPARgamma expression and activation of PPARgamma corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPARgamma inhibition by TNF-alpha.
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PMID:Regulation of PPARgamma function by TNF-alpha. 1865 73

Ghrelin (Ghr), the natural ligand of growth hormone secretagogue receptor, is principally produced by the stomach. An interesting aspect in Ghr cardiovascular effects was elicited by the identification of ghrelin and GHS (growth hormone secretagogue) receptor mRNA expression in several cardiovascular tissues and cell types. In man, Ghr administration induced lowering of blood pressure, and decreased plasma levels were reported in several pathological conditions. The present investigation was performed to elucidate ghrelin effect on contraction and proliferation of human aortic smooth muscle cells (HASMC). Ghrelin receptor expression in HASMC was evaluated by RT-PCR, and binding studies were performed to elucidate the receptor kinetics. Ghr effect on angiotensin II-induced HASMC contraction and proliferation was evaluated in vitro. In addition, involvement of cAMP, ERK, and Akt pathways was investigated. PCR documented GHS-R1a expression. Binding of [(125)I-His(9)]-Ghrelin to HASMC was saturable in a dose-dependent manner. Scatchard analysis showed a single class of binding sites (Kd 1.58+/-0.23nM, B(max) 5848+/-291fmol/10(5) cells). In competition binding, (d-Lys(3))-GHRP-6 showed a capacity to compete with [(125)I-His(9)]-Ghrelin with Ki of 4.25nM. Ghrelin was able to inhibit angiotensin II-induced proliferation and contraction in a dose-response fashion via the cAMP/PKA pathway. Our data document that Ghr affects several HASMC functions, opening the way to consider ghrelin as a possible therapeutic target in many pathological conditions associated with vascular damage and remodelling.
Atherosclerosis 2009 Mar
PMID:Ghrelin inhibits contraction and proliferation of human aortic smooth muscle cells by cAMP/PKA pathway activation. 1866 2

Fibrinogen has been implicated in atherosclerosis; in part by activating the lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4). The fibrinogen-TLR4 signalling pathway remains uncharacterised. In human macrophages fibrinogen stimulated interleukin (IL)6 expression and ERK (extracellular signal-related kinase) phosphorylation. In HEK293-CD14-MD2 cells expressing TLR4, fibrinogen induced robust phosphorylation of ERK1, p38alpha and JNK and activated transcription factors NFkappaB, Elk-1 and AP-1 (activator protein-1). The net effect of this signalling pathway was a pro-inflammatory response characterised by IL6 and TNFalpha synthesis and increased IL8, matrix metalloproteinase (MMP)1, MMP9, and MCP-1 promoter activity. Two common TLR4 mutations, D299G and T399I, render the receptor LPS hyporesponsive. The effect of fibrinogen on polymorphic variant TLR4s was markedly different; enhancing activation of kinases, transcription factors, cytokine synthesis and promoter activity. This study indicates that fibrinogen activates TLR4, explaining how fibrinogen promotes inflammatory protein expression.
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PMID:Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. 1869 Mar 51

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.
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PMID:MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. 1875 67

The urokinase plasminogen activator system with its receptor uPAR contributes to the migratory potential of macrophages, a key event in atherosclerosis. We here investigated whether free fatty acids (FFA) modify the expression for uPAR in the PMA-differentiated human monocyte/macrophage-like cell line U937. Two hundred micromolar palmitate induced a threefold increase of the uPAR mRNA expression. Although the mono- and polyunsaturated fatty acids oleate and linoleate also stimulated uPAR expression, oleate had a significantly lower effect than palmitate. The observed effects were time and dose dependent. Inhibition of PKC-and ERK-pathways resulted in a strong down-regulation of basal uPAR expression whereas the FFA induced up-regulation remained unchanged. In contrast, FFA induced uPAR up-regulation was abolished by the specific inhibition of p38 MAPK. In conclusion we demonstrate that uPAR expression in human monocytes/macrophages is differentially stimulated by FFA. These effects are partially mediated by the p38 MAP-kinase signaling pathway.
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PMID:Fatty acids differentially modify the expression of urokinase type plasminogen activator receptor in monocytes. 1876 75

Although the presence of an elevated level of serum amyloid A (SAA) has been regarded as a cardiovascular risk factor, the role of SAA on the progress of atherosclerosis has not been fully elucidated. In the present study, we investigated the effect of SAA on the production of CCL2, an important mediator of monocyte recruitment, and the mechanism underlying the action of SAA in human monocytes. The stimulation of human monocytes with SAA elicited CCL2 production in a concentration-dependent manner. The production of CCL2 by SAA was found to be mediated by the activation of NF-kappaB. Moreover, the signaling events induced by SAA included the activation of ERK and the induction of cyclooxygenase-2, which were required for the production of CCL2. Moreover, SAA-induced CCL2 induction was inhibited by a formyl peptide receptor-like 1 (FPRL1) antagonist. We also found that the stimulation of FPRL1-expressing RBL-2H3 cells induced CCL2 mRNA accumulation, but the vector-expressing RBL-2H3 cells combined with SAA did not. Taken together, our findings suggest that SAA stimulates CCL2 production and, thus, contributes to atherosclerosis. Moreover, FPRL1 was found to be engaged in SAA-induced CCL2 induction, and cyclooxygenase-2 induction was found to be essential for SAA-induced CCL2 expression. These results suggest that SAA and FPRL1 offer a developmental starting point for the treatment of atherosclerosis.
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PMID:Serum amyloid A induces CCL2 production via formyl peptide receptor-like 1-mediated signaling in human monocytes. 1876 91

Methylglyoxal (MGO) is a reactive metabolite of glucose. Since the plasma concentration of MGO is increased in diabetic patients, MGO is implicated in diabetes-associated vascular endothelial cells (ECs) injury, which might be responsible for atherosclerosis. In the present study, we examined effects of treatment of human umbilical vein ECs with MGO on EC morphology and inflammatory responses. MGO (24 h) induced cytotoxic morphological changes in a concentration-dependent manner (0-420 microM). MGO induced mRNA and protein expression of cyclooxygenase (COX)-2 in a concentration (0-420 microM)- and time (6-24 h)-dependent manner. COX-2 induction was associated with increased PGE(2) release. Acute treatment with MGO (20 min) induced concentration-dependent (0-420 microM) activation of JNK and p38 MAP kinase but not ERK or NF-kappaB. Both the JNK inhibitor SP600125 and the p38 inhibitor SB203580 prevented the MGO induction of COX-2. However, inhibiting JNK and p38 or COX-2 was ineffective to the morphological damage by MGO (420 microM, 24 h). EUK134, a synthetic combined superoxide dismutase/catalase mimetic, had no effect on MGO-induced COX-2. Present results indicated that MGO mediates JNK- and p38-dependent EC inflammatory responses, which might be independent of oxidative stress. On the other hand, MGO-induced morphological cell damage seems unlikely to be associated with COX-2-PGE(2).
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PMID:Methylglyoxal mediates vascular inflammation via JNK and p38 in human endothelial cells. 1884 28


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