Molecular modeling as a new approach to the development of urokinase inhibitors.

Proteolytic activity of urokinase plays an important role in negative remodeling of blood vessels, restenosis, tumor angiogenesis, and metastasizing, which necessitates the development of selective urokinase inhibitors. Using methods of computer modeling (docking, post processing, and direct docking) and quantum chemistry, we selected substances from the large compound database, analyzed their structures, and experimentally verified their inhibitor activity. New urokinase inhibitor candidates were proposed based on the theoretical predictions and experimental verification of compound activities.

Proteolytically inactive recombinant forms of urokinase suppress migration of endothelial cells.

Proteolytically inactive recombinant forms of urokinase (uPAHQ and amino-terminal fragment) inhibit spontaneous migration of endothelial cells; amino-terminal fragment also suppresses angiogenesis stimulated by basic fibroblast growth factor in vitro. These findings suggest the possibility of using synthesized proteolytically inactive recombinant forms of urokinase for the regulation of endothelial cell migration and suppression of neoangiogenesis.

[Analysis of morpho-functional parameters of the heart and polymorphisms of Renin-Angiotensin-aldosterone system genes in patients with different variants of the course of hypertrophic cardiomyopathy].

Background: Clinical course and prognosis of a hereditary myocardial disease hypertrophic cardiomyopathy (HCMP) is determined by multiple factors most of which have genetic nature.

Aim: To study morpho functional parameters of the heart and polymorphisms of renin angiotensin aldosterone system genes in patients with various variants of the course of HCMP: stable variant (18%), atrial fibrillation (20%), progressing variant (51%), sudden cardiac death (9%) and "terminal stage" of disease (2%). Control group comprised 55 healthy people (mean age 44.

[Genetic factors of risk of ischemic heart disease development in patients with familial hypercholesterolemia].

Unlabelled: Ischemic heart disease (IHD) develops in patients with familial hypercholesterolemia (FHC) 15-20 years earlier than in general population. However age of onset of the disease, its clinical manifestations are variable and not completely determined by cholesterol level and class of low density lipoprotein receptor mutations.

Aim: To elucidate associations of some auxiliary genetic factors -- such as C151565T, C677T, R353Q polymorphisms of glycoprotein IIIa (GPIIIa), methylenetetrahydrofolate reductase (MTHFR) and coagulation factor VII genes, respectively, -- with the presence of IHD in patients with FHC.

[The role of mutation in cardiac beta-myosin heavy chain gene in population of patients].

One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands).

[Low density lipoprotein receptor gene mutations in patients with clinical diagnosis of familial hypercholesterolemia.].

Unlabelled: Low density lipoprotein receptor (LDLR) gene mutations cause familial hypercholesterolemia which is associated with elevated risk of ischemic heart disease.

Aim: To define LDLR gene mutations in unrelated patients with heterozygous familial hypercholesterolemia in Russia.

Methods: PCR- single-strand conformation polymorphism analysis, automated DNA sequencing, and test for the presence of the apolipoprotein (apo) B-3500 mutation known to induce hereditary defect in apo-B-100.

[Multiple molecular-genetic defects in a woman with mixed hyperlipoproteinemia and early ischemic heart disease].

Aim: Analysis of genes of apolipoprotein E (apoE), LDLP receptor and methylentetrahydrofolate reductase (MTHFR) in a female patient with mixed hyperlipoproteinemia (HLP) and early ischemic heart disease (IHD).

Material And Methods: A patient with a mixed form of HLP and 5 her relatives were examined genetically. The genotype of apoE and MTHFR was determined using a restrictive analysis of PCR fragments.

[Novel lipoprotein-binding proteins p105 and p130 in smooth muscles of human vessels: structure, expression, and possible physiological role].

The expression level of two new lipoprotein-binding proteins p105 and p130 was maximal in inactive VSMC and could be suppressed by activators of proliferation. Both proteins were detected by antisera against three synthetic fragments of T-cadherin and were rendered soluble by GPI-specific phospholipase C. The findings suggest that the 105 kDa lipoprotein-binding protein is T-cadherin whereas p130 is a partially processed GPI-anchored precursor of T-cadherin.

[Antibodies against synthetic peptide fragments of T-cadherin inhibit binding of low density proteins with T-cadherin].

Potential antigenic determinants of the atypical lipoprotein-binding proteins T-cadherin (p105) and its precursor (p130) from cells of human smooth muscles were synthesized by the solid phase method according to the Fmoc-scheme. These corresponded to the 51-61, 140-160, 161-179, 260-271, 340-352, 350-362, and 370-385 sequences of p130 and were chosen on the basis of computer analysis of its antigenic structure. The conjugates of the peptides with horseradish peroxidase were used for the immunization of mice and rabbits.

[Atypical binding sites of low density lipoproteins in human vascular smooth muscle cells].

Lipoprotein-binding sites on cultured human omental vascular smooth muscle cells have been investigated. Two sites specifically binding low density lipoprotein (Kd1 = 1 microgram/ml and Kd2 = 50 micrograms/ml) were found. The properties of the high affinity site are similar to those of the previously described "classical" apo B,E-receptor.