Vladimir P. Shirinsky

Institute of Experimental Cardiology

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Alexander V. Vorotnikov

National Medical Research Center of Cardiology

Asker Y. Khapchaev

Institute of Experimental Cardiology

Konstantin G. Birukov

University of Maryland, Baltimore

D. Martin Watterson

Northwestern University

ОВ

О. В. Степанова

National Medical Research Center of Cardiology

Mikhail V. Samsonov

Institute of Experimental Cardiology

Thomas J. Lukas

Northwestern University

МВ

М. В. Сидорова

National Medical Research Center of Cardiology

Linda J. Van Eldik

University of Kentucky

Olga A. Kazakova

Institute of Experimental Cardiology

Cooperative Institutions

Institute of Experimental Cardiology

Ministry of Health of the Russian Federation

Russian Academy of Sciences

Siberian Branch of the Russian Academy of Sciences

National Medical Research Center of Cardiology

Institute of Coal of the Siberian Branch of the RAS

National Research Tomsk State University

Yaroslav-the-Wise Novgorod State University

Lomonosov Moscow State University

Kemerovo State University

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Identification of a filamin‐like protein in chicken heart muscle

FEBS Letters (1981)

V.E. Koteliansky Marina A. Glukhova Vladimir P. Shirinsky Vladimir R. Babaev V.F. Kandalenko

Center (category theory)

Research center

10.1016/0014-5793(81)80992-1

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Citations (25)

Protein kinase involved in lung injury susceptibility: Evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment

Proceedings of the National Academy of Sciences (2003)

Mark S. Wainwright Janet L. Rossi James P. Schavocky Susan E. Crawford David M. Steinhorn

Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury.

Knockout mouse

Gene knockout

10.1073/pnas.1031595100

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Citations (138)

Vascular Endothelium at the Molecular Level: From Fundamental Knowledge Toward Medical Implementation

Biomedicines (2024)

Vladimir P. Shirinsky

The concept of multiple physiologic roles played by a single layer of endothelium on the intimal face of blood vessels started gaining recognition in the 1960s [...].

10.3390/biomedicines13010002

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A Structural Study of Filamin, a Hight-Molecular-Weight Actin-Binding Protein from Chicken Gizzard

European Journal of Biochemistry (1982)

Victor Koteliansky Marina A. Glukhova Vladimir P. Shirinsky V. N. Smirnov Tatiana L. Bushueva

The structure of a filamin molecule has been studied by circular dichroism, infrared spectroscopy, scanning microcalorimetry and the inherent fluorescence of the tryptophan residues. It has been shown that the secondary structure of filamin is formed exclusively by the β form (50%); the filamin molecule consists of several domains. Some of the tryptophan residues in filamin are buried in the interior of the protein structure, whereas others are located on the surface of the filamin molecule. These results, as well as the data of previous reports, suggest the following description of the filamin molecule : the protein molecule is highly assymetric and elongated consisting of structural domains with a β-form structure interconnected by flexible regions of the polypeptide chain.

FLNA

10.1111/j.1432-1033.1982.tb05822.x

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Citations (20)

Multiple gene products are produced from a novel protein kinase transcription region

FEBS Letters (1995)

D. Martin Watterson Mark Collinge Thomas J. Lukas Linda J. Van Eldik Konstantin G. Birukov

The nonmuscle/smooth muscle myosin light chain kinase (MLCK) and the kinase related protein (KRP) that lacks protein kinase activity are myosin II binding proteins encoded in the vertebrate genome by a true gene within a gene relationship. The genomic organization and expression result in the same amino acid sequence in different molecular contexts from two different sizes of mRNA. We report here the identification and characterization of a third size class of gene products. The protein appears to be a higher molecular weight form of MLCK with additional amino terminal tail sequence which might provide differential subcellular targeting characteristics.

MAP3K7

10.1016/0014-5793(95)01048-j

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Citations (53)

Shear Stress and the AMP-Activated Protein Kinase Independently Protect the Vascular Endothelium from Palmitate Lipotoxicity

Biomedicines (2024)

Asker Y. Khapchaev Alexander V. Vorotnikov O. A. Antonova Mikhail V. Samsonov Ekaterina А. Shestakova

Saturated free fatty acids are thought to play a critical role in metabolic disorders associated with obesity, insulin resistance, type 2 diabetes (T2D), and their vascular complications via effects on the vascular endothelium. The most abundant saturated free fatty acid, palmitate, exerts lipotoxic effects on the vascular endothelium, eventually leading to cell death. Shear stress activates the endothelial AMP-activated protein kinase (AMPK), a cellular energy sensor, and protects endothelial cells from lipotoxicity, however their relationship is uncertain. Here, we used isoform-specific shRNA-mediated silencing of AMPK to explore its involvement in the long-term protection of macrovascular human umbilical vein endothelial cells (HUVECs) against palmitate lipotoxicity and to relate it to the effects of shear stress. We demonstrated that it is the α1 catalytic subunit of AMPK that is critical for HUVEC protection under static conditions, whereas AMPK-α2 autocompensated a substantial loss of AMPK-α1, but failed to protect the cells from palmitate. Shear stress equally protected the wild type HUVECs and those lacking either α1, or α2, or both AMPK-α isoforms; however, the protective effect of AMPK reappeared after returning to static conditions. Moreover, in human adipose microvascular endothelial cells isolated from obese diabetic individuals, shear stress was a strong protector from palmitate lipotoxicity, thus highlighting the importance of circulation that is often obstructed in obesity/T2D. Altogether, these results indicate that AMPK is important for vascular endothelial cell protection against lipotoxicity in the static environment, however it may be dispensable for persistent and more effective protection exerted by shear stress.

Lipotoxicity

AMP-Activated Protein Kinase

Endothelial Dysfunction

10.3390/biomedicines12020339

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Citations (2)

Identification of intimal subendothelial cells from human aorta in primary culture

Atherosclerosis (1988)

Vladimir R. Babaev Alexander S. Antonov Olga S. Zacharova Yu. A. Romanov A.V. Krushinsky

Desmin

Cell type

10.1016/0021-9150(88)90301-2

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Citations (19)

1147-P: Pseudo Insulin Resistance: Palmitate Inactivates Insulin Signaling but Stimulates Basal Glucose Uptake in 3T3-L1 Adipocytes

Diabetes (2021)

N. V. Podkuychenko Svetlana Michurina Iurii Stafeev Asker Y. Khapchaev Vladimir P. Shirinsky

Increased levels of circulating free fatty acids (FFA) is the major risk factor for type 2 diabetes in obesity. While the long-term effects of increased FFA on adipose tissue likely involve latent inflammation, the short-term effects on insulin-sensitive adipocytes are less clear. We treated fully differentiated 3T3-L1 adipocytes with increased concentrations (0.3-1 mM) of a typical FFA, palmitate, for 2 days, and measured insulin stimulation of 2-deoxyglucose (2-DG) uptake. The insulin cascade and AMPK activities, Glut-1 and Glut-4 levels were measured by western blots (WB). Glut-4 translocation was measured either by WB after cell membrane fractionation, or by fluorescence analysis after lentiviral transduction of adipocytes with Glut-4 construct containing C-terminal mCherry and outer Myc epitope insertion in the Glut-4 extracellular loop. While fluorescence of mCherry reported the total Glut-4, that of anti-Myc antibody revealed Glut-4 exposed on the plasma membrane. Palmitate dose dependently increased basal 2-DG uptake, whereas insulin-stimulated uptake and Glut-4 translocation to the plasma membrane were significantly reduced only by high (1 mM) palmitate. High palmitate did not alter Glut-1 and Glut-4 expression, but reduced IRS phosphorylation (Tyr612) and completely ceased that of Akt (Thr308/Ser473) and AS160 (Ser318) in the absence or presence of insulin, as well as phosphorylation of ACC (Ser-79) by AMPK. These results suggest that the short-term effects of palmitate on adipocytes are associated with “pseudo” insulin resistance, i.e., an increased basal glucose uptake likely due to the “pull” mechanism for increased triglyceride turnover, and the loss of insulin stimulation possibly due to fill-up of fat depots. Disclosure N. Podkuychenko: None. S. Michurina: None. I. Stafeev: None. A. Y. Khapchaev: None. V. P. Shirinsky: None. A. V. Vorotnikov: None. Funding Russian Foundation for Basic Research (20-015-00471)

GLUT4

10.2337/db21-1147-p

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Alterations in Myocardial Cytoskeletal and Regulatory Protein Expression Following a Single Doxorubicin Injection

Journal of Cardiovascular Pharmacology (2003)

Tatiana Dudnakova V. L. Lakomkin Valerie G. Tsyplenkova B. V. Shekhonin Vladimir P. Shirinsky

Immunochemical and ultrastructural studies of the rat heart after a single injection of doxorubicin (2.2 or 0.44 mg/kg) were performed. Ventricles were taken for the study 2 h and 3 weeks after injection. The light and electron microscopy and immunohistochemical determination of collagens of I, III, and IV types and fibronectin using specific antibodies were implied. Quantitive immunoblotting was used to analyze the expression levels of cytoskeletal and extracellular matrix proteins such as desmin, tubulin, vinculin, fibronectin, kinase-related protein (KRP or telokin), and smooth muscle/nonmuscle myosin light-chain kinase (MLCK). Doxorubicin (2.2 mg/kg) did not influence the relative volume and structure of collagen network but distinctly reduced the density of fibronectin distribution and decreased the content of tubulin, fibronectin, MLCK, and KRP. After 3 weeks, an increased density and extension of collagen network were observed, indicating the development of diffuse fibrosis whereas the content of tubulin and KRP increased above control level by 50 +/- 2.3% and 20 +/- 5.2%, correspondingly. Similar but less pronounced alterations were observed following the administration of 0.44 mg/kg doxorubicin. The content of MLCK after both doses consistently remained about 30% below its level in untreated animals. Isolated chick embryo cardiomyocytes subjected to doxorubicin responded by a 26% increase in KRP expression 4 days after whereas the level of tubulin expression remained unchanged. Thus, the damage of myocardium after a single injection of a therapeutic dose of doxorubicin was followed by an increased expression of selected cytoskeletal and extracellular matrix proteins, suggesting their involvement in cardiac reparation.

Vinculin

10.1097/00005344-200305000-00017

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Citations (31)

Mechano-chemical control of smooth muscle cell differentiation

Atherosclerosis (1994)

Vladimir P. Shirinsky Konstantin G. Birukov О. В. Степанова Tkachuk Va Thérèse J. Resink

10.1016/0021-9150(94)94373-7

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Citations (1)