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)

1. Total kininogen, high molecular weight kininogen and low molecular weight kininogen were quantitated as bradykinin equivalents in the blood flowing to and from the brain in patients with stenotic and occlusive carotid damage in the course of neurosurgical treatment. Although considerable improvement in blood supply of ischemic brain areas was established after surgery in all patients, improvement in postoperative neurological status was seen only in four patients (group I), while in six cases there were no or negative neurological changes (group II). 2. The biochemical study confirmed the principal difference between these two groups: 1) prior to surgery in the patients of group II, but not of group I, total kininogen in blood flowing from the brain was markedly lowered compared to its arterial level, the latter being close to normal; the decrease was due only to low molecular weight kininogen. 2) After surgery, cerebral venous total kininogen levels were significantly lowered in patients of both groups; however, for patients of group II, these changes were more pronounced and they showed a decrease in both high and low molecular weight kininogen. 3. The major involvement of low molecular weight kininogen implicates tissue kallikrein in this process. The reduction of kininogen indicates that kinin formation occurred in the cerebral intravascular space during brain ischemia and following brain reperfusion and was most likely associated with the well-known actions of kinin on cerebral vessels, i.e., vasodilatation and brain edema.
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PMID:Kininogen consumption in cerebral circulation of humans during brain ischemia and postischemic reperfusion. 774 87

It has been reported that kinins mediate part of the beneficial cardiac effects induced by treatment with angiotensin-converting enzyme inhibitors in situations such as ischemia-reperfusion injury, myocardial infarction, and cardiac hypertrophy. However, it is not known whether the heart contains an independent kallikrein-kinin system. We measured kallikrein in tissue and in the incubation medium of heart slices. Heart slices released active and total (trypsin-activatable) kallikrein into the medium (46 +/- 5 and 380 +/- 18 pg bradykinin/mg, respectively, after 1 hour and 78 +/- 6 and 654 +/- 14 pg bradykinin/mg after 2 hours, n = 7). Release was not due to tissue damage because lactate dehydrogenase, a cytosolic marker, decreased from 8.9 +/- 2.9 to 2.9 +/- 1.0 U/mg per hour. Although kallikrein was released, total tissue kallikrein in the slices did not change (423 +/- 25 pg bradykinin/mg in nonincubated slices and 370 +/- 42 pg bradykinin/mg after 2 hours, P = NS), suggesting pool replenishment. Cardiac kallikrein activity was inhibited by incubation with anti-glandular kallikrein antibodies. Pretreatment with the protein synthesis inhibitor puromycin (10 mg IP) lowered release of active kallikrein from 78 +/- 6 to 22 +/- 4 pg bradykinin/mg and total kallikrein from 654 +/- 14 to 113 +/- 9 pg bradykinin/mg (P < .001). By using reverse transcription polymerase chain reaction with kallikrein family oligonucleotide primers and a specific kallikrein probe, we found that mRNA for tissue kallikrein is present in both atrial and ventricular RNA. Kallikrein activity was also detected in primary cultures of neonatal rat atrial and ventricular cardiocytes and their incubation medium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A local kallikrein-kinin system is present in rat hearts. 820 28

The purpose of the present work was to evaluate the kallikrein-kinin system and effects of hypothermia during renal ischemia and reperfusion. Male C57BL/KSJmdb mice were subjected to 20 or 60 min ischemia for different periods of reperfusion. Our results demonstrate that short periods of ischemia followed by reperfusion did not cause significant alterations in kallikrein activity, Evans Blue (EB) extravasation, prokallikreins, myeloperoxidase activity or plasma creatinine concentration. Edema was evident at 1 h reperfusion in the treated mice, but returned to basal values after 24 h reperfusion. Kallikrein activities and EB extravasation showed a significant increase in 60 min ischemic mice. Myeloperoxidase activity in the kidney of the mice confirmed net infiltration in the group with 60 min ischemia and 24 h reperfusion. The generation of kinins and activation of matrix degrading enzymes by tissue kallikrein, liberated from both renal and infiltrated leukocytes, could be responsible at least in part for the damage observed in the kidney of mice subject to 60 min ischemia and reperfusion. The hypothermia significantly reduced the inflammatory process in the 60 min ischemic mice, and did prevent an increase in vascular permeability. Nevertheless, the tissue edema was not shown to change between normothermic and hypothermic ischemic mice.
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PMID:Renal ischemia-induced increase in vascular permeability is limited by hypothermia. 1059 59

The tissue kallikrein-kinin system is present in the heart, and kinin has been shown to have cardioprotective effects. In this study, we investigated the potential role of tissue kallikrein in myocardial ischemia/reperfusion injury through adenovirus-mediated human kallikrein gene delivery. One week after gene delivery, the rats were subjected to a 30-minute coronary occlusion followed by a 2-hour reperfusion. Kallikrein gene delivery caused significant decreases in the ratio of infarct size to ischemic area at risk (from 69.6% to 44.5%, n=10 and 8, P<0.01) and in the incidence of ventricular fibrillation (from 64.3% to 16.7%, n=14 and 24, P<0.01) compared with the group injected with control adenovirus. Kallikrein gene delivery also attenuated programmed cell death in the ischemic area compared with the control area as assessed with the terminal deoxynucleotidyl transferase-mediated nick end labeling assay (n=6, P<0.01). Icatibant, a specific bradykinin B(2) receptor antagonist, abolished these kallikrein-mediated beneficial effects. The expression of human tissue kallikrein mRNA was identified in rat heart, kidney, lung, liver, and adrenal gland. After kallikrein gene delivery, cardiac kinin and cGMP levels were significantly elevated compared with the control (29.6+/-12.7 versus 6.1+/-2.1 pg/mg protein, n=7, P<0.01; 1.30+/-0.06 versus 0.86+/-0.09 pmol/mg protein, n=5, P<0.05). These results indicate that kallikrein gene delivery protects against myocardial infarction, ventricular arrhythmias, and apoptosis in ischemia/reperfusion injury via kinin-cGMP signal pathway. The successful application of this technology may have potential therapeutic value in the treatment of coronary artery diseases.
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PMID:Kallikrein gene delivery attenuates myocardial infarction and apoptosis after myocardial ischemia and reperfusion. 1064 70

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.
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PMID:Increased kallikrein expression protects against cardiac ischemia. 1102 68

We have purified, cloned and characterized kallistatin, a tissue kallikrein-binding protein (KBP) in humans and rodents. Kallistatin is a unique serine proteinase inhibitor (serpin) with Phe-Phe residues at the P2 and P1 positions. Structural and functional analysis of kallistatin by site-directed mutagenesis and protein engineering indicate that wild-type kallistatin is selective for tissue kallikrein. Kallistatin is expressed and localized in endothelial and smooth muscle cells of blood vessels and has multiple roles in vascular function independent of the tissue kallikrein-kinin system. First, kallistatin induces vasorelaxation of isolated aortic rings and reduces renal perfusion pressure in isolated rat kidneys. Transgenic mice overexpressing rat kallistatin are hypotensive, and adenovirus-mediated gene delivery of human kallistatin attenuates blood pressure rise in spontaneously hypertensive rats. Second, kallistatin stimulates the proliferation and migration of vascular smooth muscle cells in vitro and neointima formation in balloon-injured rat arteries. Third, kallistatin inhibits the proliferation, migration and adhesion of endothelial cells in vitro and angiogenesis in the rat model of hindlimb ischemia. These results demonstrate novel roles of kallistatin in blood pressure regulation and vascular remodeling.
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PMID:Novel roles of kallistatin, a specific tissue kallikrein inhibitor, in vascular remodeling. 1125 65

Angiogenesis represents a compensatory response targeted to preserve the integrity of tissues subjected to ischemia. The aim of the present study was to examine whether reparative angiogenesis is impaired in spontaneously hypertensive rats (SHR), as a function of progression of hypertension. In addition, the potential of gene therapy with human tissue kallikrein (HK) in revascularization was challenged in SHR and normotensive Wistar-Kyoto rats (WKY) that underwent excision of the left femoral artery. Expression of vascular endothelial growth factor and HK was upregulated in ischemic hindlimb of WKY but not of SHR. Capillary density was increased in ischemic adductor muscle of WKY (from 266+/-20 to 633+/-73 capillaries/mm(2) at 28 days, P<0.001), whereas it remained unchanged in SHR (from 276+/-20 to 354+/-48 capillaries/mm(2), P=NS), thus compromising perfusion recovery as indicated by reduced plantar blood flow ratio (0.61+/-0.08 versus 0.92+/-0.07 in WKY at 28 days, P<0.05). In separate experiments, saline or 5x10(9) pfu adenovirus containing the HK gene (Ad.CMV-cHK) or the beta-galactosidase gene (Ad.CMV-LacZ) was injected intramuscularly at 7 days after the induction of ischemia. Ad.CMV-cHK augmented capillary density and accelerated hemodynamic recovery in both strains, but these effects were more pronounced in SHR (P<0.01). Our results indicate that native angiogenic response to ischemia is impaired in SHR, possibly as a result of defective modulation of endothelial cell mitogens. Supplementation with kallikrein, one of the growth factors found to be deficient in SHR, restores physiological angiogenic response utilitarian for tissue healing. Our discoveries may have important implications in vascular medicine for therapeutic benefit.
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PMID:Rescue of impaired angiogenesis in spontaneously hypertensive rats by intramuscular human tissue kallikrein gene transfer. 1146 74

Recently, therapeutic angiogenesis has been proposed as an alternative for the treatment of ischemic diseases unresponsive to conventional therapy. This strategy is based on the concept that a supply-side approach with growth factors would overcome the endogenous deficit and result in more robust collateralization. We have developed a strategy based on local delivery of human tissue kallikrein gene for potentiation of microcirculation and rescue of peripheral ischemia. Following successful application in otherwise healthy animals, the approach resulted to be of therapeutic value in rats with endothelial dysfunction caused by arterial hypertension. In addition, human tissue kallikrein prevents or rescues microvascular rarefaction caused by diabetes mellitus. In this model, human tissue kallikrein was able to stimulate vascular growth and contrast apoptosis. The strategy displays interesting pharmacological features because is devoid of obvious side effects and is effective even at low infecting doses. In addition, the neovascularization promoted by human tissue kallikrein is well organized and durable. It is reasonable to anticipate that the new approach will have a great impact in the treatment of cardiovascular ischemic complications.
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PMID:Human tissue kallikrein: a new bullet for the treatment of ischemia. 1257 Aug 6

1. Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B(2) receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery. 2. Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl-Phe-Ser-Arg-N-(2,3-dinitrophenyl)-ethylenediamine (TKI, 0.001-10 mg ml(-1)), inhibited kallikrein activity in a concentration-dependent manner in vitro. In vivo, pretreatment with TKI (30 mg kg(-1)) prevented the extravasation of plasma and the recruitment of neutrophils. 3. Similarly, the bradykinin B(2) receptor antagonists, HOE 140 (0.01-1.0 mg kg(-1)) or FR173657 (10.0 mg kg(-1)), inhibited reperfusion-induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs. 4. In a model of more severe I/R injury, HOE 140 (1.0 mg kg(-1)) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF-alpha in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL-10 in tissue and serum. 5. Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B(2) receptors. B(2) receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.
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PMID:Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury. 1274 31

Kallikrein/kinin has been shown to protect against ischemia/reperfusion-induced myocardial infarction and apoptosis. In the present study, we examined the potential neuroprotective action of kallikrein gene transfer in cerebral ischemia. Adult, male Sprague-Dawley rats were subjected to a 1-hour occlusion of the middle cerebral artery followed by intracerebroventricular injection of adenovirus harboring either the human tissue kallikrein gene or the luciferase gene. Kallikrein gene transfer significantly reduced ischemia-induced locomotor deficit scores and cerebral infarction after cerebral ischemia injury. Expression of recombinant human tissue kallikrein was identified and localized in monocytes/macrophages of rat ischemic brain by double immunostaining. Morphological analyses showed that kallikrein gene transfer enhanced the survival and migration of glial cells into the ischemic penumbra and core, as identified by immunostaining with glial fibrillary acidic protein. Cerebral ischemia markedly increased apoptotic cells, and kallikrein gene delivery reduced apoptosis to near-normal levels as seen in sham control rats. In primary cultured glial cells, kinin stimulated cell migration but inhibited hypoxia/reoxygenation-induced apoptosis in a dose-dependent manner. The effects of kinin on both migration and apoptosis were abolished by icatibant, a bradykinin B2 receptor antagonist. Enhanced cell survival after kallikrein gene transfer occurred in conjunction with markedly increased cerebral nitric oxide levels and phospho-Akt and Bcl-2 levels but reduced caspase-3 activation, NAD(P)H oxidase activity, and superoxide production. These results indicate that kallikrein gene transfer provides neuroprotection against cerebral ischemia injury by enhancing glial cell survival and migration and inhibiting apoptosis through suppression of oxidative stress and activation of the Akt-Bcl-2 signaling pathway.
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PMID:Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. 1469 96


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