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

The Fas/Fas ligand (FasL) system plays an important role in the induction of lymphoid apoptosis and has been implicated in the suppression of immune responses. Recently, there has been renewed interest in immune privilege, as it was shown that two privileged sites (the eye and testes) constitutively express FasL, which kills lymphoid cells that invade these areas. We have established murine FasL-transgenic mice (B6) under the control of the cardiac alpha-myosin heavy chain promotor, and transplanted FasL-expressing F1(B6 x C3H/HeJ) heart grafts into syngeneic (F1) and allogeneic (C3H/HeJ) recipients. FasL-expressing F1 heart allografts placed in C3H/HeJ recipients as well as FasL-expressing F1 isografts placed in nontransgenic and FasL-transgenic F1 were more rapidly rejected, and their survival was much shorter than that of nontransgenic control F1 allografts placed in C3H/HeJ. Native control and FasL-expressing hearts looked normal in mice up to 8 wk of age on hematoxylin-eosin staining. Control heart allografts undergoing ordinally acute rejection showed moderate focal lymphocyte infiltrates, while FasL-expressing F1 allografts and isografts showed massive hemorrhage, edema, and massive neutrophil infiltration as early as 1 day after transplantation. In conclusion, FasL expression and surgical procedure (ischemia/reperfusion) were synergistic in the induction of accelerated heart graft rejection, while allogenicity was not necessary. It may be necessary to find ways of controlling neutrophilic reaction/apoptosis in infiltrating lymphocytes to use FasL in clinical organ transplantation.
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PMID:Accelerated rejection of Fas ligand-expressing heart grafts. 988 28

Hypertrophic cardiac myopathy (HCM) is the leading cause of mortality in young athletes. Abnormalities in small intramural coronary arteries have been observed at autopsy in such subjects. The walls of these intramural vessels, especially in the ventricular septum, are thickened, and the lumen frequently appears narrowed. Whether these morphological characteristics have functional correlates is unknown. We studied coronary myogenic tone in a transgenic mouse model of HCM that has mutations in the cardiac alpha-myosin heavy chain gene. This transgenic mouse has a cardiac phenotype that resembles that occurring in humans. We examined the possible vascular contributions to the pathology of HCM. Septal arteries from 3- and 11-mo-old wild-type (WT) and transgenic (TG) mice were studied on a pressure myograph. The myogenic response to increased intravascular pressure in older animals was significantly reduced [maximal constriction: 32 +/- 4% (TG) and 46 +/- 4% (WT), P < 0.05]. After inhibition of endothelin receptors with bosentan, both WT and TG mice had similar increases in myogenic constriction. The sensitivity to exogenous endothelin was significantly reduced in TG mice, suggesting that the reduced myogenic constriction in HCM was due to reduced receptor sensitivity. In conclusion, we show for the first time that 1) myogenic tone in the coronary septal artery of the mouse is regulated by a basal release of endothelin, and 2) pressure-induced myogenic activation is attenuated in HCM, possibly consequent to a reduction in endothelin responsiveness. The associated reduction in coronary vasodilatory reserve may increase susceptibility to ischemia and arrhythmias.
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PMID:Coronary artery myogenic response in a genetic model of hypertrophic cardiomyopathy. 1238 27

Fructose feeding has been shown to induce the cardiac alpha-myosin heavy chain (MHC) expression and protect the heart from ischemia- and reperfusion-mediated cell injury. This study was designed to investigate the mechanism involved in the effect of this sugar on MHC gene expression and cardiac protection. Adult mice were fed with a 6-propyl-2-thiouracil (PTU) diet or PTU combined with a fructose-rich diet. PTU treatment made animals hypothyroid and that resulted in total replacement of cardiac alpha-MHC with the beta-MHC isoform. Addition of fructose in the PTU diet led to reexpression of the alpha-MHC isoform to a significant level. Similar induction of alpha-MHC expression was also seen when PTU diet was combined with resveratrol, an agonist of sirtuin (SIRT) 1 deacetylase. Analysis of heart lysate of these animals indicated that fructose feeding augmented the NAD-to-NADH ratio and the cardiac SIRT1 levels, thus suggesting a role of SIRT1 in fructose-mediated activation of alpha-MHC isoform. To analyze a direct effect of SIRT1 on MHC isoform expression, we generated transgenic mice expressing SIRT1 in the heart. Treatment of these transgenic mice with PTU diet did not lead to disappearance of alpha-MHC, as it did in the nontransgenic animals. SIRT1 overexpression also activated the alpha-MHC gene promoter in transient transfection assays, thus confirming a role of SIRT1 in the induction of alpha-MHC expression. Fructose feeding also attenuated the MHC isoform shift and blocked the cardiac hypertrophy response associated with pressure overload, which was again associated with the induction of cardiac SIRT1 levels. These results demonstrate that fructose feeding protects the heart by induction of the SIRT1 deacetylase and highlight its role in the induction of alpha-MHC gene expression.
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PMID:Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the alpha-myosin heavy chain expression. 1819 11