Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.
 ...
PMID:Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts. 929 67

The purpose of the present study was to determine whether interventions that promote kinin production or decrease kinin inactivation affect nitric oxide production in isolated canine coronary microvessels. Accordingly, bradykinin (10[-8] to 10[-5] mol/L), ramiprilat (10[-10] to 10[-8] mol/L), A23187 (10[-8] to 10[-6] mol/L), kallikrein (1 to 20 U/mL), and kininogen (0.5 to 10 microg/mL) were used to stimulate endothelium-dependent nitric oxide production. Receptor antagonists, serine protease inhibitors, and a kinin antibody were used to inactivate local kallikrein-kinin activity. Nitrite, the metabolite of nitric oxide in aqueous solution, was measured using the Griess reaction. All the agonists significantly increased nitrite release. For instance, the highest dose of bradykinin, ramiprilat, A23187, kallikrein, and kininogen markedly increased nitrite production, from 60+/-10 to 156+/-12, 153+/-11, 161+/-15, 176+/-15, and 168+/-16 pmol/mg (all P<.05), respectively. The increased nitrite production caused by these agents was not only blocked by N omega-nitro-L-arginine methyl ester (L-NAME) and HOE 140 (which blocks B2 kinin receptor) but by the kinin antibody also. For instance, nitrite production elicited by bradykinin, ramiprilat, A23187, and kininogen was reduced to 95+/-8, 87+/-8, 94+/-11, and 85+/-11 pmol/mg (all P<.05), respectively, by the kinin antibody. Carbachol-induced nitrite production (from 66+/-8 to 144+/-13) was blocked by L-NAME but not by HOE 140 or the kinin antibody. These results suggest that either increasing kininogen to promote endogenous kinin formation or inhibiting angiotensin-converting enzyme to decrease kinin breakdown, increases nitric oxide production in isolated coronary microvessels. These data indicate that a microvessel kallikrein-kinin system has an important role in the control of nitric oxide production in coronary microvessels.
 ...
PMID:Role of endothelial kinins in control of coronary nitric oxide production. 936 63

We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.
 ...
PMID:Effects of LEX032, a novel recombinant serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester induced leukocyte-endothelial cell interactions. 976 25

Lopap (Lonomia obliqua prothrombin activator protease) is a member of the lipocalin family isolated from the extract of L obliqua bristles. Lopap displays serine protease-like activities, including coagulation disturbance, cytokine secretion and antiapoptotic activity in human cultured endothelial cells. Here, we have investigated the effects of the recombinant protein (rLopap) on the inflammatory and apoptotic processes of neutrophils and endothelial cells from male Wistar rats. We found that rLopap did not induce in vivo leukocyte-endothelial interactions in the microvasculature, initial steps of leukocyte recruitment during inflammation. Incubation of rLopap with neutrophils or endothelial cells prevented apoptosis evoked by serum deprivation and induced nitric oxide (NO) production in both cell types, and increased the expression of ICAM-1 by endothelial cells. Simultaneous incubation of endothelial cells or neutrophils with rLopap and N omega-nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of NO synthases, inhibited NO production and impaired the protection on apoptosis. Differently, incubation of endothelial cells with monoclonal antibody anti ICAM-1 did not change the protection on apoptosis evoked by rLopap. Together, these results indicate that rLopap does not display inflammatory properties in vivo but inhibits apoptosis of neutrophils and endothelial cells depending, at least in part, on NO production.
 ...
PMID:Lopap: a non-inflammatory and cytoprotective molecule in neutrophils and endothelial cells. 1967 80

Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys.We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage.Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments.The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening.KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage.
...
PMID:Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations. 2646 98

Fibroblast activation protein (FAP, seprase) is a serine protease with post-proline dipeptidyl peptidase and endopeptidase enzymatic activity. FAP is upregulated in several tumor types, while its expression in healthy adult tissues is scarce. FAP molecule itself and FAP+ stromal cells play an important although probably context-dependent and tumor type-specific pathogenetic role in tumor progression. We provide an overview of FAP expression under both physiological and pathological conditions with focus on human malignancies. We also review and critically analyze the results of studies which used various strategies for the therapeutic targeting of FAP including the use of low molecular weight inhibitors, FAP activated prodrugs, anti-FAP antibodies and their conjugates, FAP-CAR T cells, and FAP vaccines. A unique enzymatic activity and selective expression in tumor microenvironment make FAP a promising therapeutic target. A better understanding of its role in individual tumor types, careful selection of patients, and identification of suitable combinations with currently available anticancer treatments will be critical for a successful translation of preclinically tested approaches of FAP targeting into clinical setting.
 ...
PMID:Targeting fibroblast activation protein in cancer - Prospects and caveats. 2977 38