Mikhail V. Samsonov

Institute of Experimental Cardiology

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Vladimir P. Shirinsky

Institute of Experimental Cardiology

Asker Y. Khapchaev

Institute of Experimental Cardiology

Alexander V. Vorotnikov

National Medical Research Center of Cardiology

Olga A. Kazakova

Institute of Experimental Cardiology

МВ

М. В. Сидорова

National Medical Research Center of Cardiology

ВЗ

В. З. Ланкин

National Medical Research Center of Cardiology

АА

А. А. Азьмуко

National Medical Research Center of Cardiology

O. A. Antonova

National Medical Research Center of Cardiology

N. V. Podkuychenko

Institute of Experimental Cardiology

МВ

Марина Владимировна Шестакова

Endocrinology Research Center

Cooperative Institutions

Institute of Experimental Cardiology

Ministry of Health of the Russian Federation

National Medical Research Center of Cardiology

Lomonosov Moscow State University

Russian Academy of Sciences

Endocrinology Research Center

Moscow State University

Federal Agency for Health and Social Development

Pavlov Institute of Physiology of the Russian Academy of Sciences

Covance (United Kingdom)

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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)

440-P: Dual Long-Term Effects of Free Fatty Acid on Human Endothelial Barrier In Vitro Are Mediated by NO, Mitochondrial ROS, and Dicarbonyl Stress

Diabetes (2021)

Mikhail V. Samsonov N. V. Podkuychenko Asker Y. Khapchaev Tatiana N. Vlasik В. З. Ланкин

In diabetes-associated hyperlipidemia, free fatty acids (FFAs) are thought to induce insulin resistance and endothelial dysfunction leading to vascular injury and cardiovascular T2DM complications. However, evidence is scarce regarding the effects of FFA on vascular endothelial barrier. We used human umbilical vein endothelial cells (HUVEC) to model, in vitro, the endothelial barrier and reveal its responses to experimental hyperlipidemia induced by long-term treatment with palmitic acid in complex with albumin. Palmitate was continuously present in the growth medium at 0.8 mM to reproduce FFA levels typical for T2DM. We developed conditions to maintain the HUVEC monolayers in the presence of the high palmitate concentration for up to 2 weeks by adding exogenous carnitine to facilitate mitochondrial β-oxidation of FFA. In this model system, palmitate readily augmented the transendothelial electric resistance (TER) of HUVEC via increased NO production by endothelial NO-synthase (eNOS). Western blots showed that palmitate neither disturbed insulin signaling cascade towards eNOS nor upregulated eNOS expression. After the initial 3-4-day rise in TER, further treatment with palmitate led to barrier stabilization and attenuation as compared to FFA-free conditions. This later phase was associated with increased ROS and malondialdehyde (MDA) accumulation, both prevented by the mitochondria-targeted antioxidant SkQ1. Treatment of HUVEC with exogenous MDA impaired the TER and barrier suggesting that accumulation of MDA-modified proteins may contribute to the barrier dysfunction upon long-term experimental hyperlipidemia. Altogether, obtained evidence suggests that prolonged exposure of vascular endothelium to high levels of palmitate compromises endothelium barrier capacity and insulin-mediated eNOS regulation turning the enzyme permanently active. Disclosure M. Samsonov: None. V. P. Shirinsky: None. N. Podkuychenko: None. A. Y. Khapchaev: None. T. Vlasik: None. V. Lankin: None. M. Skulachev: Other Relationship; Self; Mitotech LLC. I. Stafeev: None. A. V. Vorotnikov: None. M. V. Shestakova: None. Funding Russian Science Foundation (19-15-00361)

Hyperlipidemia

Malondialdehyde

Endothelial Dysfunction

Mitochondrial ROS

10.2337/db21-440-p

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Long-term experimental hyperglycemia does not impair macrovascular endothelial barrier integrity and function in vitro

Биохимия (2023)

Asker Y. Khapchaev O. A. Antonova Olga A. Kazakova Mikhail V. Samsonov Alexander V. Vorotnikov

Hyperglycemia is a hallmark of type 2 diabetes implicated in vascular endothelial dysfunction and cardiovascular complications. Many in vitro studies identified endothelial apoptosis as an early outcome of experimentally modeled hyperglycemia emphasizing cell demise as a significant factor of vascular injury. However, endothelial apoptosis has not been observed in vivo until the late stages of type 2 diabetes. Here, we studied the long-term (up to 4 weeks) effects of high glucose (HG, 30 mM) on human umbilical vein endothelial cells (HUVEC) in vitro. HG did not alter HUVEC monolayer morphology, ROS levels, NO production, and exerted minor effects on the HUVEC apoptosis markers. The barrier responses to various clues were indistinguishable from those by cells cultured in physiological glucose (5 mM). Tackling the key regulators of cytoskeletal contractility and endothelial barrier revealed no differences in the histamine-induced intracellular Ca2+ responses, nor in phosphorylation of myosin regulatory light chain or myosin light chain phosphatase. Altogether, these findings suggest that vascular endothelial cells may well tolerate HG for relatively long exposures and warrant further studies to explore mechanisms involved in vascular damage in advanced type 2 diabetes.

Endothelial Dysfunction

10.31857/s0320972523080079

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Citations (1)

Nonclinical characterization of the novel IL-1 heterodimeric fusion protein RPH-104

Immunome Research (2018)

Anastasia Dmitrieva Elena Shipaeva Margarita Schedrova Michelle Scott Yan Lavrovsky Mikhail V. Samsonov

Characterization

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Impact of Atherosclerosis‐ and Diabetes‐Related Dicarbonyls on Vascular Endothelial Permeability: A Comparative Assessment

Oxidative Medicine and Cellular Longevity (2017)

Mikhail V. Samsonov Asker Y. Khapchaev Alexander V. Vorotnikov Tatyana N. Vlasik E. V. Yanushevskaya

Malondialdehyde (MDA), glyoxal (GO), and methylglyoxal (MGO) levels increase in atherosclerosis and diabetes patients. Recent reports demonstrate that GO and MGO cause vascular endothelial barrier dysfunction whereas no evidence is available for MDA.To compare the effects of MDA, GO, or MGO on endothelial permeability, we used human EA.hy926 endothelial cells as a standard model. To study cortical cytoplasm motility and cytoskeletal organization in endothelial cells, we utilized time-lapse microscopy and fluorescent microscopy. To compare dicarbonyl-modified protein band profiles in these cells, we applied Western blotting with antibodies against MDA- or MGO-labelled proteins.MDA (150-250 μM) irreversibly suppressed the endothelial cell barrier, reduced lamellipodial activity, and prevented intercellular contact formation. The motile deficiency of MDA-challenged cells was accompanied by alterations in microtubule and microfilament organization. These detrimental effects were not observed after GO or MGO (250 μM) administration regardless of confirmed modification of cellular proteins by MGO.Our comparative study demonstrates that MDA is more damaging to the endothelial barrier than GO or MGO. Considering that MDA endogenous levels exceed those of GO or MGO and tend to increase further during lipoperoxidation, it appears important to reduce oxidative stress and, in particular, MDA levels in order to prevent sustained vascular hyperpermeability in atherosclerosis and diabetes patients.

Vascular permeability

10.1155/2017/1625130

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Citations (14)

Peculiarities of living cell response to the external stimuli revealed via quasistatic mode of atomic force microscopy

IOP Conference Series Materials Science and Engineering (2017)

M. M. Khalisov A. V. Ankudinov V. A. Penniyaynen T. E. Timoshenko K. I. Timoshchuk

The technique of atomic force microscopy allows revealing living cell morphology and mechanical properties characterization under physiologically relevant conditions. Here, we review our recent results on living cell reaction to different external influences obtained by this technique. The Bruker PeakForce QNM quasistatic mode was used to study living fibroblasts, erythrocytes, sensory neurons, and endothelial cells.

Quasistatic process

Characterization

Living cell

10.1088/1757-899x/256/1/012010

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Citations (2)

AICAR Protects Vascular Endothelial Cells from Oxidative Injury Induced by the Long-Term Palmitate Excess

International Journal of Molecular Sciences (2021)

Mikhail V. Samsonov N. V. Podkuychenko Asker Y. Khapchaev Е. Е. Ефремов E. V. Yanushevskaya

Hyperlipidemia manifested by high blood levels of free fatty acids (FFA) and lipoprotein triglycerides is critical for the progression of type 2 diabetes (T2D) and its cardiovascular complications via vascular endothelial dysfunction. However, attempts to assess high FFA effects in endothelial culture often result in early cell apoptosis that poorly recapitulates a much slower pace of vascular deterioration in vivo and does not provide for the longer-term studies of endothelial lipotoxicity in vitro. Here, we report that palmitate (PA), a typical FFA, does not impair, by itself, endothelial barrier and insulin signaling in human umbilical vein endothelial cells (HUVEC), but increases NO release, reactive oxygen species (ROS) generation, and protein labeling by malondialdehyde (MDA) hallmarking oxidative stress and increased lipid peroxidation. This PA-induced stress eventually resulted in the loss of cell viability coincident with loss of insulin signaling. Supplementation with 5-aminoimidazole-4-carboxamide-riboside (AICAR) increased endothelial AMP-activated protein kinase (AMPK) activity, supported insulin signaling, and prevented the PA-induced increases in NO, ROS, and MDA, thus allowing to maintain HUVEC viability and barrier, and providing the means to study the long-term effects of high FFA levels in endothelial cultures. An upgraded cell-based model reproduces FFA-induced insulin resistance by demonstrating decreased NO production by vascular endothelium.

Lipotoxicity

Endothelial Dysfunction

Malondialdehyde

Viability assay

10.3390/ijms23010211

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Citations (16)

Malondialdehyde but Not Methylglyoxal Impairs Insulin Signaling, NO Production, and Endothelial Barrier

Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology (2021)

Mikhail V. Samsonov N. V. Podkuychenko В. З. Ланкин Alexander V. Vorotnikov Vladimir P. Shirinsky

Malondialdehyde

Endothelial Dysfunction

Dyslipidemia

10.1134/s1990747821030089

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Citations (4)

Подавление гиперпроницаемости сосудистого эндотелия с помощью проникающих пептидных ингибиторов киназы легких цепей миозина

Биофизика (2012)

Asker Y. Khapchaev Mikhail V. Samsonov Olga A. Kazakova E. L. Vilitkevich М. В. Сидорова

На оcнове пептидного ингибитоpа киназы легкиx цепей миозина L-ПИК (Arg-Lys-Lys-Tyr- Lys-Tyr-Arg-Arg-Lys) pазpаботаны новые модифициpованные пептидные ингибитоpы. Иccле- довано иx влияние на индуциpованное тpомбином повышение пpоницаемоcти cоcудиcтого эндотелия в культуpе. Уcтановлено, что cоединения ПИК2 ([NαMeArg1]-Lys-Lys-Tyr-Lys-Tyr- Arg-(D)Arg8-Lys) и ПИК4 (H-Arg(NO2)Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2) обладают наи- более выcокой cпоcобноcтью подавлять гипеpпpоницаемоcть cоcудиcтого эндотелия, пpевоcxодя вcе извеcтные аналоги, cозданные на оcнове пептидного ингибитоpа L-ПИК. На оcновании полученныx pезультатов ПИК2 и ПИК4 могут pаccматpиватьcя как лидиpующие молекулы пpи pазpаботке новыx пептидныx лекаpcтвенныx cpедcтв для боpьбы c патологичеcким по- вышением пpоницаемоcти cоcудиcтого эндотелия.

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Long-Term Experimental Hyperglycemia Does Not Impair Macrovascular Endothelial Barrier Integrity and Function in vitro

Biochemistry (Moscow) (2023)

Asker Y. Khapchaev O. A. Antonova Olga A. Kazakova Mikhail V. Samsonov Alexander V. Vorotnikov

Endothelial Dysfunction

10.1134/s0006297923080072

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Citations (3)