The laboratory was established in 1996.
Main areas of research
- Molecular mechanisms of cell motility regulation in cardiovascular system. Currently, the main work of the laboratory in this area is the study of the molecular organization and regulation of microvascular endothelial barrier in normal conditions and in pathologies associated with vascular hyperpermeability. Because 210 kDa myosin light chain kinase (LMLCK, MLCK210) plays a key role in the barrier function of endothelium, this molecular regulator is the focus of several research projects of the laboratory:
- o the role of post-translational modifications of MLCK210, such as phosphorylation, acetylation, glutathionylation, as well as disease-associated genetic polymorphisms of MLCK210, in the regulation of its functional properties, is being studied. This work allows understand the principles of MLCK activity regulation realized in vascular cells and in the heart, and to use this knowledge to develop new pharmacological approaches to the treatment of cardiovascular diseases;
- o the role of endothelial MLCK210 in regulating the mechanical properties and mechanical sensitivity of endothelium is being elucidated. The mechanical properties of the endothelium are extremely important for its function as a key regulator of vascular tone, for maintaining normal level of vascular permeability, as well as in terms of susceptibility of vessels to atherosclerotic lesions. Understanding the principles of regulation of the stiffness and mechanical sensitivity of vascular endothelium can significantly change the approaches to the treatment of the most common cardiovascular diseases - hypertension and atherosclerosis;
- o the search for the new protein partners of MLCK210 in vascular endothelium is under way. The relationship between MLCK and other myosin-activating protein kinases, in particular, protein kinase ROCK, in regulation of endothelial permeability is being studied. These studies will identify new molecular targets that could be affected in a focused manner in order to correct endothelial dysfunction in cardiovascular diseases.
- Molecular mechanisms of regulation of cardiomyocyte contractility during ischemic conditions and oxidative stress. During ischemia and reoxygenation of the myocardium, the levels of free radicals increase in cardiomyocytes and Ca2+ transport as well as contractility are impaired due to oxidative damage to the ion-transporting protein complexes. We study the mechanisms of protection of cardiomyocytes under ischemia and oxidative stress. We anticipate that these studies will decipher the molecular mechanisms of impaired myocardial contractility in a large group of cardiac patients and propose new treatments of chronic heart failure - a disease for which there is currently no effective treatment.
- Search and development of new biosimilar drugs for cardiology. Fundamental studies of the molecular mechanisms of cell motility in normal and pathological conditions make it possible to identify key processes that can prevent or stop a disease. In some cases, nature itself “suggests” which molecules perform these functions in the body. These include low molecular weight compounds, peptides, proteins, miRNAs, and even genes. The widespread use of natural and biosimilar molecules as drugs is considered the nearest future of practical medicine.
Modern technologies, such as molecular and cellular biology, protein biochemistry and immunochemistry, proteomics and bioinformatics, various types of light microscopy and video microscopy, atomic force microscopy, are widely used in laboratory research. Experimental models of vascular permeability in vitro, models based on transgenic and standard laboratory animals are used.
The most significant research results of recent years
- In the joint studies with colleagues from the United States, we discovered the high molecular weight isoform of the myosin light chain kinase (LMLCK; MLCK210), a key regulator of motility of non-muscle cells, including vascular endothelium. In subsequent works, the properties of MLCK210 unique N-terminal domain were first described. Sites of interaction with microfilaments and microtubules were found in this domain. When studying the properties of Kinase-Related Protein (KRP) from smooth muscles, which also exists as the C-terminal domain of MLCK, it was found that KRP / KRP domain interacts with myosin II, the main molecular motor of the cell. Taken together, these and other data allowed us to propose a model of the functional organization of MLCK210 as the cytoskeleton integrator and motility organizer in non-muscle cells. Due to coordinated action of MLCK210 functional domains, non-muscle cells perform divergent motile reactions, such as adhesion to the substrate and migration, endocytosis and secretion, membrane receptor capping, cytokinesis, and others. MLCK210 plays important role in specialized forms of cell motility such as permeability of endothelial and epithelial monolayers. It triggers the contraction of vascular endothelial cells within the monolayer and the formation of intercellular gaps, which correlates with impaired endothelial barrier function and the development of microvascular hyperpermeability in a large number of pathological conditions. The identification of MLCK210 as a key activator of vascular hyperpermeability allowed begin the development of new endothelial protectors and antiedemic drugs for emergency medicine.
- Investigating, together with German scientists, the role of KRP protein in smooth muscles, we concluded that this protein could perform the function of the universal inhibitor of protein kinases that activate smooth muscle myosin, such as MLCK, ROCK, DAPK, etc. This data highlighted a new aspect of regulation of smooth muscle contraction involving KRP protein. Perhaps, KRP-domain of MLCK210 plays similar role in non-muscle cells - endothelium, epithelium, leukocytes, etc.
- In collaboration with the laboratory of peptide synthesis, a family of original cell-penetrating peptide inhibitors of MLCK was designed. One of the family members, PIK7, is currently undergoing preclinical studies as a candidate drug that protects endothelial monolayer and blocks the development of endothelial hyperpermeability under stress. Based on PIK7, a novel endothelial protector can be designed to combat life-threatening conditions - acute edema of the lungs and brain, as well as ischemic and reperfusion tissue damage during surgical operations and organ transplantation.
- The model of isolated cardiomyocytes derived from animals with experimental heart failure showed a positive effect of synthetic biosimilar peptide molecules that reproduce the C-terminal fragment of the hormone apelin on intracellular Ca2+ transport and contractility of cardiac cells. Based on apelin-like peptide, an innovative drug for the treatment of heart failure is designed at the Institute of Experimental Cardiology.
- Using the model of isolated adult rat cardiomyocytes subjected to hypoxia and reoxygenation, the cardioprotective effect of dinitrosyl iron complexes (DNIC) with glutathione under oxidative stress was shown. Based on this compound, the antihypertensive drug Oxacom® was created at the National Medical Research Center for Cardiology. The efficacy of Oxacom® to relieve hypertensive crises is currently being tested in patients. In collaborative studies with the laboratory of experimental heart pathology, we provided evidence that Oxacom® could be effectively used to protect ischemic myocardium during cardiac surgery using artificial circulation and in patients with chronic ischemic heart disease. Together with Professor A.F. Vanin (Institute of Chemical Physics named after N.N. Semenov, RAS), a new version of DNIC based on ethyl ether of glutathione was designed that demonstrated higher cardioprotective activity than Oxacom®.
- Scientific results produced by the members of the laboratory are presented in multiple publications in top Russian and peer review international scientific journals and in monographs. Research and development accomplishments of the laboratory are protected by five patents of the Russian Federation.