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INSTITUTE OF PHYSIOLOGY CAS

Cutting-edge science for health

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Transcription factor Hif-1a is required for the correct development of the sympathetic nervous system and innervation of the heart (16.1. 2020)

Hypoxia-inducible factor 1 (Hif-1) is the master regulator of transcriptional responses of cells to decreased oxygen availability. Research teams of the Institutes of Biotechnology and Physiology CAS and the 1st Medical Faculty UK showed that genetic mutation of the Hif-1a gene suppresses the embryonic development of preganglionic and postganglionic neurons of the sympathetic nerve system and negatively affects sympathetic innervation of the heart that plays a primary role in the regulation of heart rate and contractility. Mice with conditional deletion of Hif-1a gene exhibited coronary artery anomalies and decreased cardiac contractile function. These data indicate that deregulation of the transcription factor Hif-1a can result in serious cardiovascular diseases associated with the autonomic nervous system dysbalance and open the way to a development of new therapeutic strategies.

Impaired sympathetic innervation of hearts with Hif-1a deletion (Hif1aCKO): Immunohistochemical staining of tyrosine hydroxylase (TH) in posterior view of hearts, and quantification of TH-positive fibers per ventricle area in E16.5 control and Hif1aCKO littermates.

Bohuslavová, Romana - Čerychová, Radka - Papoušek, František - Olejníčková, Veronika - Bartoš, M. - Goerlach, A. - Kolář, František - Sedmera, David - Semenza, G.L. - Pavlínková, Gabriela: HIF-1 alpha is required for development of the sympathetic nervous system. Proceedings of the National Academy of Sciences of the United States of America. Roč. 116, č. 27 (2019), s. 13414-13423. ISSN 0027-8424, IF: 9.580, 2018. DOI: 10.1073/pnas.1903510116

The resistance of pancreatic beta cells to oxidative stress, which accompanies diabetes type 2, can be increased by mitochondria-targeted antioxidants (15.1. 2020)

Increased blood glucose induces secretion of the hormone insulin in β cells of Langerhans islets in the pancreas. his response is regulated by redox signalization, where a slight increase of reactive oxygen species (ROS) serves as a messenger for the regulation of protein pathways leading to the secretion of insulin from insulin granules in β cells. On the contrary, excessive production of ROS causes pathological oxidative stress which accompanies many diseases such as diabetes type 2. Oxidative stress can be suppressed by enhancing antioxidant defense.  Mitochondria are important energy factories of the cells and are also one of the main sources of ROS. In the present paper, we tested the effect of new antioxidant molecules, namely SkQ, S3QEL and S1QEL, which target the sites of ROS production in mitochondria. We uncovered the detailed mechanism of their effect in various sites of mitochondria, where they specifically prevent ROS formation and thus show antioxidant role. However, they can also have pro-oxidative properties. This is dependent on energy metabolism of the cell and thus substrate availability (for example glucose). As an example, SkQ antioxidant shows an antioxidant property when a cell has excessive energy substrate supply which happens in vivo after a meal, i.e. postprandial. If there is a shortage of energy substrate, happening in vivo during fasting, SkQ behaves in short-term pro-oxidatively and can even increase already established oxidative stress. Detailed knowledge of the activity of these selected antioxidant in pancreatic β cells can be used in diabetes treatment.

Figure of possible SkQ activity: Suggested mechanisms for antioxidant action of matrix-targeted antioxidant SkQ: (a) antioxidative two-electron reduction of SkQ to SkQH2 plus regeneration (oxidation of SkQH2) within the mitochondrial electron transport complex I, based on reference [1]; (b) antioxidative two-electron reduction of SkQ to SkQH2 within complex III and regeneration at the complex I, based on reference [1]

Plecitá-Hlavatá; Lydie - Engstová; Hana - Ježek; Jan - Holendová; Blanka - Tauber; Jan - Petrásková; Lucie - Křen; Vladimír - Ježek; Petr . Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic beta-cells . Oxidative Medicine and Cellular Longevity. 2019; 2019(2019)); 1826303 . IF = 4.868.

A promising pharmacological approach in cardiovascular disease prevention (9.7. 2019)

Epoxyeicosatrienoic acids (EETs), cytochrome P450 epoxygenase metabolites of arachidonic acid, represent a promising pharmacological approach in cardiovascular disease prevention. In our study, cardioprotective effects of a novel, stable and orally active agonistic 14,15-EET analog EET-B on the progression of post-ischemic heart failure  was examined in spontaneously hypertensive rats (SHR), a pre-clinical rodent model of human essential hypertension. SHR were subjected to myocardial infarction and the effects of continuous EET-B treatment before and after MI on post-ischemic left ventricular function, myocardial fibrosis and inflammation were analyzed. As EET-based therapies can attenuate the progression of HF by mechanisms involving activation of heme oxygenase-1, its immunopositivity in viable myocytes of the ischemic myocardium was also determined. We demonstrated that EET-B treatment improved post-ischemic left ventricular function, markedly increased heme oxygenase-1 immunopositivity in cardiomyocytes subjected myocardial infarction and reduced cardiac inflammation and fibrosis. These findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce remodeling in SHR subjected to myocardial infarction.

8.Neckář, Jan - Khan, M. A. H. - Gross, G. J. - Cyprová, Michaela - Hrdlička, Jaroslav - Kvasilová, A. - Falck, J. R. - Campbell, W. B. - Sedláková, Lenka - Škutová, Šárka - Olejníčková, Veronika - Gregorovičová, Martina - Sedmera, David - Kolář, František - Imig, J. D. Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats. Clinical science. Roč. 133, č. 8 (2019), s. 939-951. ISSN 0143-5221, IF: 5,237 (2018).

Small amounts of inorganic nitrate or beetroot provide substantial protection from salt-induced Increases in blood pressure (4.4. 2019)

Adding tiny amounts of beetroot or dietary nitrate to salty food products might help prevent high blood pressure, according to a preliminary study of rats.

To reduce the risk of salt-induced hypertension, medical authorities have emphasized dietary guidelines promoting high intakes of potassium and low intakes of salt that provide molar ratios of potassium to salt of ≥1:1. However, during the past several decades, relatively few people have changed their eating habits sufficiently to reach the recommended dietary goals for salt and potassium. Thus, new strategies that reduce the risk of salt-induced hypertension without requiring major changes in dietary habits would be of considerable medical interest. In the current studies in a widely used model of salt-induced hypertension, the Dahl salt-sensitive rat, we found that supplemental dietary sodium nitrate confers substantial protection from initiation of salt-induced hypertension when the molar ratio of added nitrate to added salt is only ≈1:170. Provision of a low molar ratio of added nitrate to added salt of ≈1:110 by supplementing the diet with beetroot also conferred substantial protection against salt-induced increases in blood pressure. The results suggest that on a molar basis and a weight basis, dietary nitrate may be ≈100× more potent than dietary potassium with respect to providing substantial resistance to the pressor effects of increased salt intake. Given that leafy green and root vegetables contain large amounts of inorganic nitrate, these findings raise the possibility that fortification of salty food products with small amounts of a nitrate-rich vegetable concentrate may provide a simple method for reducing risk for salt-induced hypertension.

Effects of supplemental sodium nitrate or beetroot on salt-induced increases in blood pressure. A, Time course of 24-h averages of systolicarterial pressure. B, Time course of 24-h averages of diastolic arterial pressure. C, Mean changes in systolic arterial pressure induced by salt loading. D, Mean changes in diastolic arterial pressure induced by salt loading. *P < 0.05.

Morris Jr, R. Curtis - Pravenec, Michal - Šilhavý, Jan - DiCarlo, E. Stephen - Kurtz, W. Theodore: Small amounts of inorganic nitrate or beetroot provide substantial protection from salt-induced increases in blood pressure. Hypertension. Roč. 73, 2019. doi: 10.1161/HYPERTENSIONAHA.118.12234. [Epub ahead of print]. ISSN 0194-911X, IF: 6.857.

The effect of gut microbiome on expression of genes involved in regulation of stress response in chronic stress (11.2. 2019)

The scientists from the Institutes of Physiology and Microbiology CAS have shown, that absence of gut microbiota leads to altered behavior in social conflict and changes of expression of genes involved in regulation of stress response in chronically stressed mice.

Mammals are naturally colonized by microorganisms, commonly referred as the microbiome. Substantial fraction of the microbiome represent bacteria. Some bacteria are capable of synthetizing chemical substances, such as hormones or neurotransmitters, and thus influence the host both on local and whole-organism level. Disruption of the microbiome is associated with several immune and neuropsychiatric disorders and stress may disrupt the balance between the host and the microbiome. When facing potential danger, stress response acts towards maintaining the homeostasis by activating variety of mechanisms such as sympatho-adrenal system or the hypothalamo-pituitary-adrenal (HPA) axis. Acute stress is generally not harmful, however when prolonged or poorly managed, it can lead to serious side effects.

For studying the effects of microbiome on the host the germ-free mice are used as animal model. It is known that microbiome alters the behavior and can alter humoral response to acute stress. In collaboration with our colleagues from the Institute of Microbiology CAS we have focused on the effects of chronic psychosocial stress in germ-free mice. Our results have shown that the absence of microbiome affects the murine behavior in social conflicts (Fig. 1) and modulates the expression of genes involved in regulation of stress response in adrenal gland (Fig. 2), local paracrine signalization in colon and expression of cytokines in mesentery lymph nodes and colon. This study contributes to understanding the crosstalk between microbiota and the host brain, especially during chronic stress.

Fig. 1. Time spent in individual defensive behavioral patterns (upright posture, freezing and escape/flight) and in total defensive behavior (B) of specific pathogen-free (SPF) and germ-free (GF) mice. Data are expressed as the means ± SEM; *P < 0.05.

Fig. 2. Responses of genes encoding adrenal steroidogenesis, catecholamine biogenesis and glucocorticoid metabolism following social defeat in specific pathogen-free (SPF) and germ-free (GF) mice. MC2R, melanocortin 2 receptor; StAR, steroidogenic acute regulatory protein; Cyp11a1, cholesterol side-chain cleavage enzyme; TH, tyrosine hydroxylase; PNMT, phenylethanolamine N-methyltransferase; 11HSD1 and 11HSD2, 11b-hydroxysteroid dehydrogenase type 1 and type 2. The data are expressed as the means ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.

Vodička, Martin - Ergang, Peter - Hrnčíř, Tomáš - Mikulecká, Anna - Kvapilová, Pavlína - Vagnerová, Karla - Šestáková, Blanka - Fajstová, Alena - Hermanová, Petra - Hudcovic, Tomáš - Kozáková, Hana - Pácha, Jiří: Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress. Brain Behavior and Immunity. Roč. 73, Oct 2018 (2018), s. 615-624. ISSN 0889-1591, IF: 6.306, 2017.

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