Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Implants of collagen-fibronectin gels containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVECs) induce the formation of human endothelial cell (EC)/murine vascular smooth muscle cell (VSMC) chimeric vessels in immunodeficient mice. Microfil casting of the vasculature 60 d after implantation reveals highly branched microvascular networks within the implants that connect with and induce remodeling of conduit vessels arising from the abdominal wall circulation. Approximately 85% of vessels within the implants are lined by Bcl-2-positive human ECs expressing VEGFR1, VEGFR2, and Tie-2, but not integrin alpha(v)beta(3). The human ECs are seated on a well formed human laminin/collagen IV-positive basement membrane, and are surrounded by mouse VSMCs expressing SM-alpha actin, SM myosin, SM22alpha, and calponin, all markers of contractile function. Transmission electron microscopy identified well formed EC-EC junctions, chimeric arterioles with concentric layers of contractile VSMC, chimeric capillaries surrounded by pericytes, and chimeric venules. Bcl-2-HUVEC-lined vessels retain 70-kDa FITC-dextran, but not 3-kDa dextran; local histamine rapidly induces leak of 70-kDa FITC-dextran or India ink. As in skin, TNF induces E-selectin and vascular cell adhesion molecule 1 only on venular ECs, whereas intercellular adhesion molecule-1 is up-regulated on all human ECs. Bcl-2-HUVEC implants are able to engraft within and increase perfusion of ischemic mouse gastrocnemius muscle after femoral artery ligation. These studies show that cultured Bcl-2-HUVECs can differentiate into arterial, venular, and capillary-like ECs when implanted in vivo, and induce arteriogenic remodeling of the local mouse vessels. Our results support the utility of differentiated EC transplantation to treat tissue ischemia.
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PMID:Induction, differentiation, and remodeling of blood vessels after transplantation of Bcl-2-transduced endothelial cells. 1562 6

Physiological stresses (heat, hemodynamics, genetic mutations, oxidative injury and myocardial ischemia) produce pathological states in which protein damage and misfolded protein structures are a common denominator. The specialized proteins family of antistress proteins - molecular chaperons (HSPs) - are responsible for correct protein folding, dissociating protein aggregates and transport of newly synthesized polypeptides to the target organelles for final packaging, degradation or repair. They are inducible at different cell processes such as cell division, apoptosis, signal transduction, cell differentiation and hormonal stimulation. HSPs are involved in numerous diseases including cardiovascular pathologies, revealing changes of expression and cell localization. We studied the possible changes in expression level of abundant mitochondrial chaperon Hsp60 and main human cytochrome P450 monooxygenase (2E1 isoform) at dilated cardiomyopathy (DCM) progression at the end stage of heart failure using Western blot analysis. The ischemic and normal humans' hearts were studied as control samples. We observed the decrease of Hsp60 level in cytoplasmic fraction of DCM- and ischemia-affected hearts' left ventricular and significant increase of Hsp60 in mitochondrial fractions of all hearts investigated. At the same time we detected the increase of P450 2E1 expression level in ischemic and dilated hearts' cytoplasmic fractions in comparison with normal myocardium and no detectable changes in microsomal fractions of hearts investigated which could be linked with increased level of oxidative injury for DCM heart muscle. In addition, all the changes described are accompanied by significant decrease of ATPase activity of myosin purified from DCM-affected heart in comparison with normal and ischemic myocardia as well. The data obtained allow us to propose a working hypothesis of functional link between antistress (HSPs) and antioxidative (cytochromes) systems at DCM progression.
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PMID:Molecular chaperone, HSP60, and cytochrome P450 2E1 co-expression in dilated cardiomyopathy. 1576 99

Endothelial progenitor cells (EPCs) home to sites of tissue injury and differentiate into mature endothelial cells. Their transfer feasibility has been proven in models of hindlimb ischemia and myocardial infarction. We investigated, the effect of delivery of spleen-derived EPC in a rat model of inflammatory-mediated myocardial damage. Male Lewis rats (N=25) were immunized against myosin. Healthy donor Lewis rats were sacrificed, their spleens harvested, separated on Ficoll gradient centrifugation, and grown on fibronectin coated plates with endothelial cell medium for 5 days. Ten days after myosin immunization, spleen cell derived EPC were collected, and labeled 2 x 10(7) cells per rat were injected into the femoral vein of diseased rats. Cell transplantation was repeated twice, 2 and 4 weeks after initial cell transfer. Rats with inflammatory-mediated cardiomyopathy exhibited a significant mobilization of EPC from the bone marrow to the periphery and their ability to adhere to fibronectin, mature endothelial cells and cultured cardiomyocytes was significantly reduced when compared to healthy rats. Transfer of EPC resulted in a functional improvement in cardiac performance evident by higher fractional shortening by echocardiography (a 15% increase). Histological studies exhibited reduced scar tissue and thickened ventricular walls in rats receiving EPC as compared with untreated animals. EPC transfer is effective in attenuating myocardial damage in a model of non-ischemic dilated cardiomyopathy.
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PMID:Transfer of endothelial progenitor cells improves myocardial performance in rats with dilated cardiomyopathy induced following experimental myocarditis. 1612 96

Complement receptor type 2 (CR2) is a receptor that serves as an important interface between the complement system and adaptive immunity. Recent studies have shown that CR2 is also centrally involved in innate immunity, and one key area is the development of potentially pathogenic natural antibodies that target neo-epitopes revealed in ischemic tissue undergoing reperfusion. Mice lacking either total immunoglobulins or CR2 alone are protected from the development of ischemia-reperfusion injury, and this effect can be reversed by introducing CR2-sufficient B-1 cells or by transferring polyclonal natural IgM antibody from wild type mice as well as monoclonal antibodies that recognize phospholipids, DNA or non-muscle myosin. We will report at the XXI ICW an additional membrane-associated protein to which pathogenic IgM antibodies are directed. Whether B cells producing these natural antibodies are differentially selected in CR2-deficient mice is as yet not well understood, and the complement-related mechanism(s) whereby this differential repertoire selection process could occur have yet to be explored in any detail. In addition to this important role in innate immunity, CR2 can also act as a receptor for other components or activators of innate immunity. One such component is interferon-alpha, an anti-viral cytokine that binds CR2 and induces a component of its mRNA signature in B cells through this receptor. Other potential CR2 ligands are DNA and DNA-containing complexes such as chromatin. The biologic role of these CR2 interactions with interferon-alpha and DNA-containing complexes is not well understood, but may be important in the development of the autoimmune disease systemic lupus erythematosus that is characterized by enhanced interferon-alpha levels and loss of self tolerance to DNA-containing self antigens.
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PMID:Complement receptor 2, natural antibodies and innate immunity: Inter-relationships in B cell selection and activation. 1687 64

Earlier demonstrated cardio-protection by ATP-loaded liposomes (ATP-L) was further improved by attachment of cardiac myosin-specific monoclonal 2G4 antibody onto the surface of ATP-L. ATP-IL were infused for 1 min duration before starting the global ischemia for 25 min followed by reperfusion for 30 min in an isolated rat heart. The left ventricular developed pressure at the end of reperfusion in ATP-IL group significantly recovered to above 80% of the baseline compared to ca 25% in the Kreb's-Henseleit (KH) buffer, ca 60% in the IL, and ca 70% in the ATP-L treated groups. At the end of the reperfusion, left ventricular end diastolic pressure significantly reduced to 15 +/- 2 mmHg in ATP-IL group compared to 59 +/- 6 mmHg in the KH buffer, 31 +/- 4 mmHg in the IL and 23 +/- 3 mmHg in the ATP-L controls. The extent of preservation depended on the amount of the antibody present on the surface of the ATP-IL.
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PMID:ATP-loaded immunoliposomes specific for cardiac myosin provide improved protection of the mechanical functions of myocardium from global ischemia in an isolated rat heart model. 1688 47

The purpose of this study was to characterize microneurovascular (MNV) muscle transplants immunohistochemically up to 10 years after transfer. Histological data was related to long-term functional outcome. The study comprised 17 patients with a mean age of 41 years suffering from complete unilateral long-lasting facial paralysis. A two-stage procedure was performed between 1986 and 2001. The gracilis, latissimus dorsi, and serratus muscles were used in four, eight, and five patients, respectively. Eighteen biopsy samples were taken from MNV muscle grafts during secondary refinement procedures. In one patient, the tissue samples were collected at two different time points. Immunohistochemistry testing revealed muscle fiber type distribution (anti-myosin fast), proliferating satellite cells (Ki-67), and reinnervation (S-100). Muscle atrophy was assessed histomorphometrically. In a recent study, patient characteristics and the function of the flap were evaluated. Histological data were compared with clinical data and long-term functional outcomes of the patients. In biopsy samples taken 1-10 (mean 31 months) years after MNV muscle transfer, the mean muscle fiber diameter was 38 (range 14-70) microm, indicating a 40% decrease compared with control values. Muscle atrophy was not type-specific and the mean percentage of type II fibers was not altered. Individual variation was, however, considerable. Proliferative activity of satellite cells was seen in 60% of the samples but it tended to decline with an increase in follow-up time. All samples showed intramuscular reinnervation. In statistical analysis severe atrophy correlated with prolonged intraoperative ischemia (P=0.04). The good long-term functional outcome correlated with dominance of fast fibers in muscle grafts (P=0.03). Atrophy tended to be more pronounced in the serratus than in the other muscles (ns). In summary, despite dense muscle reinnervation, morphology of the muscle is not fully restored after muscle transfer. Ischemia time affects muscle morphology. Adaptation of the graft to fast-twitch muscle activity favors better mimic function. The proliferative activity of satellite cells declines with prolonged follow-up time.
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PMID:Long-term adaptation of human microneurovascular muscle flaps to the paralyzed face: an immunohistochemical study. 1706 8

Acute myocarditis is a non-ischemic inflammatory disease of the myocardium for which there is currently no specific treatment. We have previously shown that mesenchymal stem cells (MSC) can ameliorate heart injury during acute ischemia and in dilated cardiomyopathy; however, the therapeutic potential in acute myocarditis is unclear. In this study, we investigated the ability of MSC to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Ten-week-old male Lewis rats were injected with porcine myosin to induce myocarditis. Cultured MSC (3x10(6) cells/rat) were injected intravenously 7 days after myosin injection. At 3 weeks, myosin injection resulted in severe inflammation and significant deterioration of cardiac function. MSC transplantation attenuated increases in CD68-positive inflammatory cells and monocyte chemoattractant protein-1 (MCP-1) expression in myocardium, and improved cardiac function in this model. Furthermore, myocardial capillary density was higher in myocarditis tissue, and was further increased by MSC transplantation. In vitro, cultured adult rat cardiomyocytes were injured in response to MCP-1, whereas this effect was attenuated by MSC-derived conditioned medium, suggesting cardioprotective effects of MSC acting in a paracrine manner. MSC transplantation attenuated myocardial injury and dysfunction in a rat model of acute myocarditis, at least in part through paracrine effects of MSC.
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PMID:Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. 1710 Nov 47

In view of the high incidence of heart failure and sudden cardiac death, efforts in the development of compounds which target-specific mechanisms such as a reduced expression of SERCA2, the Ca2+ pump of sarcoplasmic reticulum, of hypertrophied cardiomyocytes of pressure-overloaded or infarcted hearts should be strengthened. Lead compounds for correcting a dysregulated gene expression are the carnitine palmitoyltransferase-1 (CPT-1) inhibitors etomoxir and oxfenicine. Since bypassing the CPT-1 inhibition by a medium-chain fatty acid diet had a lesser effect on myosin V1 proportion than on lipid droplet number, one has to infer also other mechanisms such as PPARalpha activation (FOXIB/PPARalpha). In view of the intricate interrelationship between depressed pump function and malignant arrhythmias, stimulation of endogenous antiarrhythmogenic mechanisms linked to an enhanced production of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could potentially provide alternatives to the administration of 1 g EPA and DHA ethyl esters (minimum 84% EPA + DHA) for secondary prevention of myocardial infarction. The apparently greater efficacy of omega-3 fatty acids in post-myocardial infarction patients (GISSI-Prevention study) compared with ICD patients (SOFA study) can be attributed to the greater ischemia-induced release of membrane-bound EPA and DHA and a better compliance (one vs. four capsules daily).
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PMID:Acute heart failure--basic pathomechanism and new drug targets. 1714 74

The glutamic acid to lysine mutation at the 22nd amino acid residue (E22K) in the human cardiac myosin regulatory light chain (RLC) gene causes familial hypertrophic cardiomyopathy (FHC) with a phenotype of midventricular obstruction and septal hypertrophy. Our recent histopathology results have shown that the hearts of transgenic E22K mice (Tg-E22K) resemble those of human patients, demonstrating enlarged interventricular septa and papillary muscles. In this study, we show no effect of the E22K mutation on the kinetics of mutated myosin in its ATP-powered interaction with fluorescently labeled single actin filaments compared to nontransgenic or transgenic wild-type (Tg-WT) control mice. Likewise, no change in cross-bridge dissociation rates (g(app)) was observed in freshly skinned papillary muscle fibers. In contrast, maximal force and ATPase were decreased approximately 20% in Tg-E22K skinned papillary muscle fibers and intracellular [Ca2+] and force transients were significantly decreased in intact papillary muscle fibers from Tg-E22K compared to Tg-WT mice. Moreover, energy metabolism measured in isolated working Tg-E22K mouse hearts perfused under conditions of physiologically relevant levels of metabolic demand was similar in Tg-E22K and control hearts before and after 20 min of no-flow ischemia. Our results suggest that the pathological response observed in the E22K myocardium might be triggered by mutation induced changes in the properties of the RLC Ca2+-Mg2+ site, the state of the Ca2+/Mg2+ occupancy and consequently the Ca2+ buffering ability of the RLC. By decreasing the affinity of the RLC for Ca2+, the E22K mutation most likely promotes a Mg2+-saturated RLC producing less force and ATPase than the Ca2+-saturated RLC of WT fibers. Decreased Ca2+ binding may also lead to faster Ca2+ dissociation kinetics in Tg-E22K intact fibers resulting in decreased duration and amplitude of [Ca2+] and force transients. These changes when placed in vivo would result in higher workloads and consequently cardiac hypertrophy.
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PMID:Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients. 1760 8

We determined the effects of peroxynitrite (ONOO-) on cardiac myosin, actin, and thin filaments in order to more clearly understand the impact of this reactive compound in ischemia/reperfusion injury and heart failure. Actin filaments, native thin filaments, and alpha-cardiac myosin from rat hearts were exposed to ONOO- in the presence of 2 mM bicarbonate. Filament velocities over myosin, calcium sensitivity, and relative force generated by myosin were assessed in an in vitro motility assay in the absence of reducing agents. ONOO- concentrations > or =10 microM significantly reduced the velocities of thin filaments or bare actin filaments over alpha-cardiac myosin when any of these proteins were exposed individually. These functional deficits were linearly related to the degree of tyrosine nitration, with myosin being the most sensitive. However, at 10 microM ONOO- the calcium sensitivity of thin filaments remained unchanged. Cotreatment of myosin and thin filaments, analogous to the in vivo situation, resulted in a significantly greater functional deficit. The load supported by myosin after ONOO- exposure was estimated using mixtures experiments to be increased threefold. These data suggest that nitration of myofibrillar proteins can contribute to cardiac contractile dysfunction in pathologic states in which ONOO- is liberated.
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PMID:Peroxynitrite inhibits myofibrillar protein function in an in vitro assay of motility. 1804 43


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