Disease relevance of SERPINA4

• The kallistatin cDNA encoding the mature peptide was expressed in Escherichia coli [1].
• We also compared immunoreactive kallistatin levels in vitreous fluids from 18 patients with diabetic retinopathy and 17 non-diabetic subjects [2].
• The difference in distribution and levels of ITK and kallistatin in protein and mRNA in patients with inflammatory bowel disease (IBD) compared to controls suggest a role in inflammatory state [3].
• The profile of tissue kallikrein (TK) and its inhibitor, kallistatin was evaluated in patients with active ulcerative colitis (UC) and Crohn's disease (CD) [3].
• This study introduces the potential significance of kallistatin in directly regulating blood pressure to reduce hypertension [4].

Psychiatry related information on SERPINA4

• PI 4-kinase activity was significantly lower in Alzheimer's disease patients relative to age-matched controls or patients with Parkinson's disease [5].

High impact information on SERPINA4

• This increased vascular permeability was reversed by treatment with intravenous human C1INH, with a Kunitz domain plasma kallikrein inhibitor (DX88), and with a bradykinin type 2 receptor (Bk2R) antagonist (Hoe140) [6].
• These results indicate that kallistatin is a potent vasodilator which may function directly through a vascular smooth muscle mechanism independent of an endothelial bradykinin receptor [4].
• Neither Hoe 140 nor Nomega-nitro--arginine methyl ester, a nitric oxide synthase inhibitor, affected vasorelaxation induced by kallistatin [4].
• Infusion of purified kallistatin (0.07-1.42 nmol/kg) into cannulated rat jugular vein produced a 20-85 mmHg reduction of blood pressure in a dose-dependent manner [4].
• The aim of this study is to evaluate if kallistatin has a direct effect on the vasculature and on blood pressure homeostasis [4].

Chemical compound and disease context of SERPINA4

• Kallistatin: a novel human serine proteinase inhibitor. Molecular cloning, tissue distribution, and expression in Escherichia coli [1].
• Recombinant rat kallistatin produced in E. coli is able to bind to tissue kallikrein, and the interaction is inhibited by heparin [7].
• Clonogenic survival assay was used to determine the effect of orobol, a potent PI4-kinase inhibitor, on DDP sensitivity in human ovarian carcinoma 2008 cells [8].
• Moreover, it was demonstrated that previous administration of a kallikrein inhibitor (aprotinin) or bradykinin B2 receptor antagonist (HOE-140) significantly reduces the edema and hypotension in response to LOCBE, using mouse paw edema bioassay and mean arterial blood pressure analysis, respectively [9].
• First, 17 patients with mild to moderate essential hypertension maintained on a 130-mmol/day diet, received either nifedipine (10 mg orally) or placebo during a 6-h infusion of the kallikrein inhibitor aprotinin (2 x 10(6) KIU) or saline as control [10].

Biological context of SERPINA4

• Kallistatin is a new member of the serpin superfamily with a unique reactive site P1-P1' of Phe-Ser [1].
• Four potential glycosylation sites are found in the translated amino acid sequence of kallistatin [1].
• We found that an intravenous bolus injection of human kallistatin caused a rapid, potent, and transient reduction of mean arterial blood pressure in anesthetized rats [4].
• Kallistatin also caused dose-dependent vasodilation of the renal vasculature in the isolated, perfused rat kidney [4].
• Human kallistatin mutants with 19 different amino acid substitutions at each P1, P2, or P3 residue were created and purified to compare their kallikrein binding activity [11].

Anatomical context of SERPINA4

• In salivary glands, kallistatin and kallikrein mRNAs were also colocalized in serous acinar cells, and the kallikrein transcript was further localized to striated and interlobular ducts [12].
• Immunoreactive kallistatin and kallikrein were colocalized in acinar cells of the human pancreas by immunohistochemistry [12].
• Immunoreactive kallistatin was localized in serous acinar and demilune cells of salivary glands and kallikrein was localized to the epithelium of striated and interlobular ducts [12].
• Linear dose-dependent curves of the tissue extracts of the retina and choroid are parallel to that of purified human kallistatin, suggesting their immunological identity [2].
• The kallistatin mRNA was identified in the ciliary muscle, lens epithelial cells, all the layers of retina cells, optic nerve, choroid and vascular endothelial cells [2].

Associations of SERPINA4 with chemical compounds

• We have recently purified a novel human serine proteinase inhibitor (serpin), designated as kallistatin, which binds to tissue kallikrein and inhibits kallikrein's kininogenase and amidolytic activities [1].
• Tissue kallikrein and kallistatin gene transcripts were identified using digoxigenin-labeled riboprobes at the cellular level [13].
• Identification of a major heparin-binding site in kallistatin [14].
• Two synthetic peptides, containing clusters of positive-charged residues, one derived from the F helix and the other from the region encompassing the H helix and C2 sheet of kallistatin, were used to assess their heparin binding activity [14].
• A novel human tissue kallikrein inhibitor designated as kallistatin has been purified from plasma to apparent homogeneity by polyethylene glycol fractionation and successive chromatography on heparin-Agarose, DEAE-Sepharose, hydroxylapatite, and phenyl-Superose columns [15].

Physical interactions of SERPINA4

• Kallistatin is a newly identified serine proteinase inhibitor (serpin) which binds to tissue kallikrein and inhibits its enzymatic activity in vitro [13].
• Therefore, the kinetics of kallikrein inactivation and the formation of kallikrein inhibitor complexes were studied in normal plasma and in plasma depleted of either alpha 2-macroglobulin (alpha 2M), C1 inhibitor, or antithrombin (AT III) [16].
• The inhibitor present in the kallikrein-inhibitor complex formed was identified as alpha 1-antitrypsin by two-dimensional immunoelectrophoresis [17].

Regulatory relationships of SERPINA4

• Kallistatin is a serine proteinase inhibitor (serpin) that specifically inhibits tissue kallikrein [18].
• Kallistatin inhibits human tissue kallikrein's activity toward kininogen and tripeptide substrates [15].

Other interactions of SERPINA4

• In the present studies, we have cloned a full-length cDNA encoding kallistatin from human liver RNA by the polymerase chain reaction [1].
• The acute toxicity and proteolytic activity of BLTX were strongly inhibited by aprotinin, a kallikrein inhibitor, suggesting that its toxicity is due to a kallikrein-like activity of the venom [19].
• CD31 immunostaining of tumor sections showed a decreased number of blood vessels in the kallistatin-treated group as compared to the control [20].
• Taken together, these results indicate that the heparin-binding domain, but not the reactive site loop of kallistatin, is essential for inhibiting VEGF-induced angiogenesis [21].
• Kininogen and kallistatin levels were unchanged [22].

Analytical, diagnostic and therapeutic context of SERPINA4

• A genomic Southern blot using the full-length kallistatin cDNA probe revealed simple banding patterns suggesting the gene encoding kallistatin is single-copied [1].
• The cloning of human kallistatin cDNA established the identity of the novel kallikrein inhibitor and its expression in a functional form in E. coli provides means for studying its structure-function relationship through protein engineering [1].
• To understand the role of kallistatin in modulating tissue kallikrein's function in vivo, we examined the anatomical relationship between human tissue kallikrein and kallistatin in the kidney by in situ hybridization histochemistry [13].
• Immunoreactive human renal kallikrein and kallistatin levels were measured in the kidney and urine by immunoassays using specific antibodies [13].
• Human kallistatin and tissue kallikrein levels were measured by ELISA and radioimmunoassay, respectively, in pancreatic and salivary tissue extracts, and in pancreatic fluid and saliva [12].

References