Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151814 (coronary occlusion)
 3,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heparin is a highly sulfated polysaccharide consisting of a repeating disaccharide structure as found in other glycosaminoglycanes. The intravenous and subcutaneous formulation of the drug is routinely used for its well-known, time-honored antithrombotic effect. However, available evidences linking heparin to angiogenesis raise the possibility of a therapeutically relevant antiischemic effect of the drug. Molecular biology data show that in a hypoxic milieu heparin could facilitate angiogenesis through interactions with a family of polypeptide growth factor mitogens that stimulate endothelial cell proliferation. Experimental data suggest that heparin can augment collateral circulation when combined with other potentially angiogenetic factors, such as repeated ischemia, coronary occlusion, or physical exercise. Clinical data, although very initial, encompassing a total of only 41 heparin-treated patients with coronary artery disease, suggest that heparin facilitates collateral development stimulated by exercise-induced myocardial ischemia in humans. According to the heparin-collateral hypothesis, the mechanism of action of heparin as an antiischemic medication would be independent of its anticoagulant action. The molecular targets of heparin are Factor Xa and IIa for antithrombotic action, heparin-binding growth factors (including fibroblast growth factor and vascular endothelial growth factor) for angiogenesis. The antithrombotic effect is not linked to a cellular target, whereas the angiogenetic effect directly stimulates endothelial cells. The molecular cofactor required for effect is antithrombin III for antithrombosis, and possibly endogenous adenosine for angiogenesis. The therapeutic effect is achieved within minutes or hours for antithrombosis, and within weeks or months for angiogenesis.
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PMID:The coronary angiogenetic effect of heparin: experimental basis and clinical evidence. 937 49

Our objective was to delineate the temporal sequence of mitogenic activity in myocardial interstitial fluid (IF) during enhancement of collateral growth. Collateral development in chronically instrumented dogs was induced by eight 2-min coronary occlusions/day for 21 days. Collateralization was assessed by measurement of blood flow in the region distal to a total coronary occlusion. Myocardial IF was obtained periodically from an intramyocardial catheter, and mitogenic activity was assessed by proliferative response of cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) to the IF. Three experiments were conducted to test that the mitogenic activity is induced by protein growth factors: 1) protein digestion of the myocardial IF with Pronase-coupled latex beads; 2) heat inactivation (boiling) of the IF; and 3) neutralization of the mitogenic activity with antibodies for basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Blood flow was reconstituted to baseline levels during occlusion after 3 wk of repetitive coronary occlusions. After initiation of occlusion the mitogenic activity of the myocardial IF on VSMC and EC increased up to days 12-14 and was reduced on days 19-23. Pronase treatment and heat inactivation blocked the mitogenic effect. Treatment with antibodies for bFGF and VEGF neutralized the proliferative response to the myocardial IF at specific times. bFGF antibody inhibited the mitogenic effect significantly on days 12-14. VEGF antibody neutralized the mitogenicity of the myocardial IF on day 7, days 12 and 13, and days 19 and 20 significantly. We conclude that myocardial IF harvested from ischemic myocardium is highly mitogenic up to 2 wk after initiation of repetitive coronary occlusions. After 3 wk of ischemia, the degree of mitogenic activity for VSMC and EC was decreased from peak levels. The antibodies could not neutralize the mitogenic effect of the myocardial IF during this time period. These results suggest that mitogens are expressed during various stages of collateral development in a time-dependent manner, that the mitogens are proteinaceous in nature, and that bFGF and VEGF are released into the myocardial IF.
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PMID:Repetitive coronary artery occlusions induce release of growth factors into the myocardial interstitium. 972 2

Brief periods of coronary occlusion render the affected myocardium more tolerant to the otherwise devastating effects of long coronary occlusion. Besides this phenomena, called ischemic preconditioning, short periods of ischemia cause a regional dysfunction, namely myocardial stunning. The molecular mechanisms of both syndromes are not very well understood. We therefore investigated the expression of genes which may be involved in cardioprotection or repair processes. Using our porcine model of ischemia and reperfusion we were able to show an induction of genes coding for transcription factors (proto-oncogenes), for proteins involved in repair processes (heat shock genes), for proteins implicated in the calcium homeostasis (calcium-handling genes) and for growth factors. We could show that the increased mRNA levels are due to an enhanced transcriptional activity and not to a prolonged half-life of the transcripts. The angiogenic growth factor vascular endothelial growth factor (VEGF) represents an exception. It exhibits--in addition to a HIF-motif (Hypoxia Inducible Factor) in its promoter/enhancer--a protein binding region in its 3' UTR which when occupied renders the mRNA more stable. However to what extent the expression of the distinct genes contributes to the cardioprotective effect of ischemic preconditioning or myocardial stunning can only be presumed. Increased mRNA stability can be confered via adenosine which is produced during ischemia by ATP-breakdown. The demasking of unknown genes--via differential display reverse transcription polymerase chain reaction (DDRT-PCR)--should provide a more comprehensive view of the mechanisms underlying both processes.
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PMID:Gene expression after short periods of coronary occlusion. 977 84

Vascular endothelial growth factor-B (VEGF-B) is closely related to VEGF-A, an effector of blood vessel growth during development and disease and a strong candidate for angiogenic therapies. To further study the in vivo function of VEGF-B, we have generated Vegfb knockout mice (Vegfb(-/-)). Unlike Vegfa knockout mice, which die during embryogenesis, Vegfb(-/-) mice are healthy and fertile. Despite appearing overtly normal, Vegfb(-/-) hearts are reduced in size and display vascular dysfunction after coronary occlusion and impaired recovery from experimentally induced myocardial ischemia. These findings reveal a role for VEGF-B in the development or function of coronary vasculature and suggest potential clinical use in therapeutic angiogenesis.
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PMID:Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. 1066 23

An efficient gene delivery system is a prerequisite for myocardial gene therapy. Among the various procedures studied so far, catheter-based percutaneous gene delivery to the myocardium through the coronary vessels seems the most relevant to routine clinical practice; however, the optimal conditions remain to be determined. We selectively infused adenoviral vectors encoding luciferase (1 x 10(9) PFU) or beta-galactosidase (1 x 10(10) PFU) into coronary arteries of adult rabbits in various experimental conditions. Coronary artery occlusion for 30 sec, during and after adenovirus delivery, was required to observe luciferase activity in the target area of the circumflex artery (4.0 +/- 1.0 x 10(5) vs. 1.1 +/- 0.2 x 10(4) RLU/mg with and without coronary occlusion, respectively, p < 0.01, and 1.0 +/- 0.1 x 10(3) RLU/mg using nonselective infusion). When adenoviruses were delivered using high-pressure infusion (82 +/- 12 vs. 415 +/- 25 mmHg before and during infusion, respectively, p < 0.01), luciferase activity increased to 8.5 +/- 2.5 x 10(5) RLU/mg (p < 0.05 vs coronary occlusion alone). Coronary venous sinus occlusion with saline buffer retroinfusion starting before and during anterograde adenovirus delivery resulted in a further 4.7-fold increase in luciferase activity (4.4 +/- 0.8 x 10(6) RLU/mg, p < 0.01) with 5-25% blue-stained myocytes in the target area, compared with 0-5% with the other procedures. Histamine or VEGF-A(165) pretreatment, used to increase vascular permeability, slightly increased gene transfer efficiency (8.5 +/- 2.0 x 10(5) and 9.0 +/- 2.5 x 10(5) RLU/mg respectively, p < 0.05 vs. coronary occlusion alone). We conclude that catheter-mediated adenoviral gene transfer to cardiac myocytes through coronary vessels can be a very efficient procedure for myocardial gene therapy, particularly when the vector residence time and perfusion pressure in the vessels are increased.
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PMID:How to optimize in vivo gene transfer to cardiac myocytes: mechanical or pharmacological procedures? 1153 64

Current technologies make it possible to study thousands of genes simultaneously in the same biological sample - an approach termed gene expression profiling. Several techniques, including (i) differential display, (ii) serial analysis of gene expression (SAGE), (iii) subtractive hybridization and (iv) gene microarrays (Gene Chips), have been developed. Recently, gene profiling was applied in studying the mechanisms of ischemic injury and ischemic preconditioning. In the case of reversible ischemia caused by one or several brief transient episodes of complete coronary occlusion (as with ischemic preconditioning), or with a more prolonged but partial coronary ligation, many up-regulated genes were related to the "cell survival program". Protective genes included mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK 3), heat shock proteins 70, 27, 22, B-crystalline, vascular endothelial growth factor, inducible nitric oxide synthase and plasminogen activator inhibitors 1 and 2. With permanent coronary occlusion lasting from 24 h to several weeks, and resulting in a true myocardial infarction (MI), the list of up-regulated genes included those related to remodeling (e.g., collagens I and III, fibronectin, laminin) and apoptosis (Bax), while many down-regulated genes were related to major energy-generating pathways in the heart, namely, fatty acid metabolism. Gene expression profiling experiments have resulted in the discovery of two different genetic programs in the heart, namely, a protective program activated upon brief episodes of transient ischemia and an injury-related one activated in response to irreversible ischemic injury. Searching for factors turning on protective genes, and turning down injury-related ones, is a justifiable approach in developing new therapeutic strategies aimed to fight ischemic heart disease.
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PMID:Gene expression profiling--a new approach in the study of myocardial ischemia. 1282 86

Pretreatment of rodent hearts with platelet-derived growth factor (PDGF)-AB decreases myocardial injury after coronary occlusion. However, PDGF-AB cardioprotection is diminished in older animals, suggesting that downstream elements mediating and/or synergizing the actions of PDGF-AB may be limited in aging cardiac vasculature. In vitro PDGF-AB induced vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 expression in 4-mo-old rat cardiac endothelial cells, but not in 24-mo-old heart cells. In vivo injection of young hearts with PDGF-AB increased densities of microvessels staining for VEGF and its receptor, Flk-1, and Ang-2 and its receptor, Tie-2, as well as PDGF receptor (PDGFR)-alpha. In older hearts, PDGF-AB-mediated induction was primarily limited to PDGFR-alpha. Studies in a murine cardiac transplantation model demonstrated that synergist interactions of PDGF-AB plus VEGF plus Ang-2 (PVA) provided an immediate restoration of senescent cardiac vascular function. Moreover, PVA injection in young rat hearts, but not PDGF-AB alone or other cytokine combinations, at the time of coronary occlusion suppressed acute myocardial cell death by >50%. However, PVA also reduced the extent of myocardial infarction with an age-associated cardioprotective benefit (4-mo-old with 45% reduction vs. 24-mo-old with 24%; P < 0.05). These studies showed that synergistic cytokine pathways augmenting the actions of PDGF-AB are limited in older hearts, suggesting that strategies based on these interactions may provide age-dependent clinical cardiovascular benefit.
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PMID:Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat heart. 1500 92

Enhanced external counterpulsation (EECP) is an effective noninvasive treatment of coronary artery disease. Its mechanism of action remains unknown. An acute coronary occlusion dog model was created to explore the angiogenic effect of EECP. After coronary occlusion, 12 dogs were randomly assigned to either EECP (n = 6) or control (n = 6). Immunohistochemical studies of alpha-actin and von Willebrand factor (vWF) were used to detect newly developed microvessels. Systemic and local vascular endothelial growth factor (VEGF) were identified by ELISA and reverse transcriptase PCR analysis. There was a significant increase in the density of microvessels per squared millimeter in the infarcted regions of the EECP group compared with the control group (vWF, 15.2 +/- 6.3 vs. 4.9 +/- 2.1, P < 0.05; alpha-actin, 11.8 +/- 5.3 vs. 3.4 +/- 1.2, P < 0.05). The positive-stained area per squared micrometer also increased significantly (alpha-actin, 6.6 x 10(3) +/- 2.9 x 10(3) microm2 vs. 0.6 x 10(3) +/- 0.5 x 10(3) microm2, P < 0.05; vWF, 5.7 x 10(3) +/- 1.9 x 10(3) microm2 vs. 1.7 x 10(3) +/- 1.4 x 10(3) microm2, P < 0.05). Immunohistochemical staining and reverse transcriptase PCR analysis documented a significant increase in VEGF expression. These factors associated with angiogenesis corresponded to improved myocardial perfusion by 99mTc-sestamibi single-photon emission computed tomography. Angiogenesis may be a mechanism of action for the improved myocardial perfusion demonstrated after EECP therapy.
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PMID:Angiogenic effects of long-term enhanced external counterpulsation in a dog model of myocardial infarction. 1611 71

We assessed (1) angiogenic factors in patients with stable angina and longstanding (> or =24 months) total occlusion of a single coronary artery and (2) the relation between plasma levels of angiogenic factors and the development of collateral vessels as evaluated by coronary angiography. Plasma concentrations of vascular endothelial growth factor (VEGF(165)), fibroblast growth factor, placenta-derived growth factors (PlGFs), and hepatocyte growth factor were assessed in 96 patients with stable angina and longstanding (> or =24 months) total occlusion of a single coronary artery. According to coronary angiographic results, 18 patients had no visible collaterals (group 0), 21 patients had visible collaterals but no filling of the recipient epicardial vessel (group 1), and 57 patients showed filling (partial or complete) of the recipient epicardial vessel by collaterals (group 2). Plasma VEGF(165) and PlGF concentrations were higher in group 1 than in groups 0 and 2 (VEGF(165) 75 pg/ml, range 24 to 105, vs 23 pg/ml, range 15 to 29, and 19 pg/ml, range 10 to 41, respectively, F = 5.53, p = 0.006; PlGF 35 pg/ml, range 3.5 to 105, vs 1 pg/ml, range 1 to 38, and 1 pg/ml, range 1 to 5, respectively, F = 7.09, p = 0.008). Plasma VEGF(165) and PlGF levels were similar in groups 0 and 2. There was no significant difference in plasma levels of fibroblast and hepatocyte growth factor concentrations across the 3 groups. In conclusion, plasma levels of angiogenic growth factors differ among patients with stable angina pectoris and longstanding total coronary occlusion.
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PMID:Relation of various plasma growth factor levels in patients with stable angina pectoris and total occlusion of a coronary artery to the degree of coronary collaterals. 1686 40

Effects of ischaemic preconditioning (IP) on the mobilisation and recruitment of haematopoietic (HSCs) and mesenchymal stem (MSC) cells were determined in porcine coronary occlusion/reperfusion. Thirty-three pigs underwent percutaneous occlusion of the left anterior descending coronary artery (LAD) for 90 minutes (min), followed by 120 min reperfusion. IP was performed in 16 of the 33 pigs by two cycles of 5 min balloon occlusion/reperfusion prior to the 90 min occlusion (group IP vs. group C). Peripheral blood and myocardial tissue concentration of bone marrow origin HSCs (characterised by coexpression of CD31+, CD90+, CD45+) and MSCs (characterised by coexpression of CD44+, CD90+, CD45-) were measured by flow cytometry in the early phase of IP. Plasma/serum levels of stem cell mobilisation factors (stromal cell-derived factor-1a [SDF-1a], vascular endothelial growth factor [VEGF], tumour necrosis factor a[TNF-a] and interleukin-8 [IL-8]) were measured. IP led to a significant increase in circulating HSCs as compared with the group C (475 +/- 233 vs. 281 +/- 264 /ml, p=0.032) in the early phase of IP. In contrast, a rapid and prolonged decrease in level of circulating MSCs was observed in group IP as compared with group C (19 +/- 12 vs. 32 +/- 17 /ml, p=0.015). The recruitment of HSCs and MSCs in infarct and border zone was significantly greater in IP group, indicating a faster homing of MSCs as compared with the rate of mobilisation. Rapid increase in VEGF, TNF-a and IL-8 levels was induced by IP, which, however, was not correlated with the levels of circulating SCs. In conclusion, IP resulted in differential mobilisation and recruitment of HSCs and MSCs in the early phase of cardioprotection.
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PMID:Differential effect of ischaemic preconditioning on mobilisation and recruitment of haematopoietic and mesenchymal stem cells in porcine myocardial ischaemia-reperfusion. 2039 Feb 33


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