TY  - JOUR
AU  - Đokić, Vladimir
AU  - Gostimirović, Miloš
AU  - Rajković, Jovana
AU  - Rakočević, Jelena
AU  - Labudović-Borović, Milica
AU  - Janković, Svetlana
AU  - Stanišić, Jelena
AU  - Kostić, Milan
AU  - Đurić, Miloš
AU  - Gojković-Bukarica, Ljiljana
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/11226
AB  - Background/Aim. A substantial line of evidence indicates that Kv4.2 and Kv4.3 channels are the major components of rapid transient-outward potassium currents (A-type cur-rents). It is speculated that those currents may be involved in the maintenance of the membrane potential, as well as in the regulation of propagation and frequency of action potentials. However, very little is known about the presence and function of A-type currents in human vascular smooth muscles such as the human umbilical vein (HUV). Bearing in mind its crucial role in the proper fetal oxygenation, the aim of the study was to determine whether Kv4.2 and Kv4.3 potassium channels are present in HUV smooth muscle and to investigate potential alterations of their expression during maternal pathological conditions such as gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH). Methods. Healthy, diabetic, and hypertensive pregnancies were subjects of this investigation. Each group consisted of 6 HUV samples obtained from 6 normal pregnancies, 6 pregnancies with GDM, and 6 with PIH. After pharmacology analysis, immunohistochemistry (IH) and Western blot were performed. Results. IH revealed similar expression patterns of both, Kv4.2 and Kv4.3 subunits in HUV smooth muscle in all groups of patients. Results obtained by Western blot were in agreement with IH staining. The expression of Kv4.2 and Kv4.3 subunits were not significantly different between the groups. Conclusion. Collective-ly, this is the first study that demonstrated the presence of Kv4.2 and Kv4.3 potassium channels in the HUV smooth muscle and their preservation during GDM and PIH pregnancies. These channels are most likely major components of rapid A-type currents that may be relevant for maternal-fetus blood flow and hence fetal development. In addition, they may represent sensors for detecting hemodynamic and/or metabolic changes in the local environment.
AB  - Uvod/Cilj. Značajan niz dokaza ukazuje na to da su kanali Kv4.2 i Kv4.3 glavne komponente brzih prolazno- ispravljačkih struja kalijuma (struje tipa A). Pretpostavlja se da bi te struje mogle da budu uključene u održavanje membranskog potencijala ćelije, kao i u regulaciju propagacije i učestalosti akcionih potencijala. Međutim, vrlo malo se zna o prisustvu i funkciji struje tipa A u glatkim mišićima krvnih sudova čoveka, kao što je humana umbilikalna vena (HUV). S obzirom na njenu ključnu ulogu u adekvatnoj oksigenaciji fetusa, cilj rada bio je da se utvrdi da li su podtipovi kalijumovih kanala Kv4.2 i Kv4.3 prisutni u glatkim mišićima HUV-a i da se istraže potencijalne promene njihove ekspresije tokom patoloških stanja majke – gestacijskog dijabetesa melitusa (GDM) i arterijske hipertenzije (AH) izazvane trudnoćom (AHT). Metode. U istraživanje su uključene HUV sakupljene posle trudnoće zdravih porodilja, onih čije trudnoće su bile komplikovane GDM i AH. Svaka grupa sastojala se od 6 uzoraka HUV-a dobijenih iz 6 zdravih trudnoća, 6 trudnoća komplikovanih GDM i 6 trudnoća komplikovanih AH. Nakon farmakoloških analiza, urađene su imunohistohemijska (IH) analiza i Western blot. Rezultati. Primenom IH analize pokazan je sličan obrazac ekspresije obe podjedinice Kv4.2 i Kv4.3 kanala u glatkim mišićima HUV-a u svim grupama trudnica. Rezultati dobijeni Western blot-om bili su u skladu sa IH bojenjem. Ekspresija podjedinica Kv4.2 i Kv4.3 nije se značajno razlikovala između grupa trudnica. Zaključak. Ovo je prema našim saznanjima prva studija kojom je pokazano prisustvo Kv4.2 i Kv4.3 kalijumovih kanala u glatkim mišićima HUV-a zdravih porodilja, kao i onih porodilja čija je trudnoća bila praćena prisustvom GDM ili AHT. Ti kanali su najverovatnije glavne komponente brzih struja A-tipa, koji mogu biti relevantni za protok krvi majke i ploda i na taj način delovati protektivno za razvoj fetusa. Takođe, oni mogu predstavljati senzitivne pokazatelje hemodinamskih i/ili metaboličkih promena u lokalnoj fetomaternalnoj sredini.
T2  - Vojnosanitetski pregled
T1  - Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies
T1  - Ekspresija kalijumovih kanala Kv4.2 i Kv4.3 u humanim pupčanim venama zdravih trudnica, trudnica sa gestacijskim dijabetesom melitusom i trudnica sa gestacijskom hipertenzijom
VL  - 80
IS  - 1
SP  - 71
EP  - 77
DO  - 10.2298/VSP211014005D
ER  - 

@article{
author = "Đokić, Vladimir and Gostimirović, Miloš and Rajković, Jovana and Rakočević, Jelena and Labudović-Borović, Milica and Janković, Svetlana and Stanišić, Jelena and Kostić, Milan and Đurić, Miloš and Gojković-Bukarica, Ljiljana",
year = "2023",
abstract = "Background/Aim. A substantial line of evidence indicates that Kv4.2 and Kv4.3 channels are the major components of rapid transient-outward potassium currents (A-type cur-rents). It is speculated that those currents may be involved in the maintenance of the membrane potential, as well as in the regulation of propagation and frequency of action potentials. However, very little is known about the presence and function of A-type currents in human vascular smooth muscles such as the human umbilical vein (HUV). Bearing in mind its crucial role in the proper fetal oxygenation, the aim of the study was to determine whether Kv4.2 and Kv4.3 potassium channels are present in HUV smooth muscle and to investigate potential alterations of their expression during maternal pathological conditions such as gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH). Methods. Healthy, diabetic, and hypertensive pregnancies were subjects of this investigation. Each group consisted of 6 HUV samples obtained from 6 normal pregnancies, 6 pregnancies with GDM, and 6 with PIH. After pharmacology analysis, immunohistochemistry (IH) and Western blot were performed. Results. IH revealed similar expression patterns of both, Kv4.2 and Kv4.3 subunits in HUV smooth muscle in all groups of patients. Results obtained by Western blot were in agreement with IH staining. The expression of Kv4.2 and Kv4.3 subunits were not significantly different between the groups. Conclusion. Collective-ly, this is the first study that demonstrated the presence of Kv4.2 and Kv4.3 potassium channels in the HUV smooth muscle and their preservation during GDM and PIH pregnancies. These channels are most likely major components of rapid A-type currents that may be relevant for maternal-fetus blood flow and hence fetal development. In addition, they may represent sensors for detecting hemodynamic and/or metabolic changes in the local environment., Uvod/Cilj. Značajan niz dokaza ukazuje na to da su kanali Kv4.2 i Kv4.3 glavne komponente brzih prolazno- ispravljačkih struja kalijuma (struje tipa A). Pretpostavlja se da bi te struje mogle da budu uključene u održavanje membranskog potencijala ćelije, kao i u regulaciju propagacije i učestalosti akcionih potencijala. Međutim, vrlo malo se zna o prisustvu i funkciji struje tipa A u glatkim mišićima krvnih sudova čoveka, kao što je humana umbilikalna vena (HUV). S obzirom na njenu ključnu ulogu u adekvatnoj oksigenaciji fetusa, cilj rada bio je da se utvrdi da li su podtipovi kalijumovih kanala Kv4.2 i Kv4.3 prisutni u glatkim mišićima HUV-a i da se istraže potencijalne promene njihove ekspresije tokom patoloških stanja majke – gestacijskog dijabetesa melitusa (GDM) i arterijske hipertenzije (AH) izazvane trudnoćom (AHT). Metode. U istraživanje su uključene HUV sakupljene posle trudnoće zdravih porodilja, onih čije trudnoće su bile komplikovane GDM i AH. Svaka grupa sastojala se od 6 uzoraka HUV-a dobijenih iz 6 zdravih trudnoća, 6 trudnoća komplikovanih GDM i 6 trudnoća komplikovanih AH. Nakon farmakoloških analiza, urađene su imunohistohemijska (IH) analiza i Western blot. Rezultati. Primenom IH analize pokazan je sličan obrazac ekspresije obe podjedinice Kv4.2 i Kv4.3 kanala u glatkim mišićima HUV-a u svim grupama trudnica. Rezultati dobijeni Western blot-om bili su u skladu sa IH bojenjem. Ekspresija podjedinica Kv4.2 i Kv4.3 nije se značajno razlikovala između grupa trudnica. Zaključak. Ovo je prema našim saznanjima prva studija kojom je pokazano prisustvo Kv4.2 i Kv4.3 kalijumovih kanala u glatkim mišićima HUV-a zdravih porodilja, kao i onih porodilja čija je trudnoća bila praćena prisustvom GDM ili AHT. Ti kanali su najverovatnije glavne komponente brzih struja A-tipa, koji mogu biti relevantni za protok krvi majke i ploda i na taj način delovati protektivno za razvoj fetusa. Takođe, oni mogu predstavljati senzitivne pokazatelje hemodinamskih i/ili metaboličkih promena u lokalnoj fetomaternalnoj sredini.",
journal = "Vojnosanitetski pregled",
title = "Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies, Ekspresija kalijumovih kanala Kv4.2 i Kv4.3 u humanim pupčanim venama zdravih trudnica, trudnica sa gestacijskim dijabetesom melitusom i trudnica sa gestacijskom hipertenzijom",
volume = "80",
number = "1",
pages = "71-77",
doi = "10.2298/VSP211014005D"
}

Đokić, V., Gostimirović, M., Rajković, J., Rakočević, J., Labudović-Borović, M., Janković, S., Stanišić, J., Kostić, M., Đurić, M.,& Gojković-Bukarica, L.. (2023). Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies. in Vojnosanitetski pregled, 80(1), 71-77.
https://doi.org/10.2298/VSP211014005D

Đokić V, Gostimirović M, Rajković J, Rakočević J, Labudović-Borović M, Janković S, Stanišić J, Kostić M, Đurić M, Gojković-Bukarica L. Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies. in Vojnosanitetski pregled. 2023;80(1):71-77.
doi:10.2298/VSP211014005D .

Đokić, Vladimir, Gostimirović, Miloš, Rajković, Jovana, Rakočević, Jelena, Labudović-Borović, Milica, Janković, Svetlana, Stanišić, Jelena, Kostić, Milan, Đurić, Miloš, Gojković-Bukarica, Ljiljana, "Expression of Kv4.2 and Kv4.3 potassium channels in human umbilical veins from normal, diabetic and hypertensive pregnancies" in Vojnosanitetski pregled, 80, no. 1 (2023):71-77,
https://doi.org/10.2298/VSP211014005D . .

TY  - JOUR
AU  - Đokić, Vladimir
AU  - Janković, Svetlana
AU  - Labudović-Borović, Milica
AU  - Rakočević, Jelena T.
AU  - Stanišić, Jelena
AU  - Rajković, Jovana
AU  - Novaković, Radmila
AU  - Kostić, Milan
AU  - Đurić, Miloš
AU  - Gostimirović, Miloš
AU  - Gojković-Bukarica, Ljiljana
PY  - 2020
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/9048
AB  - Voltage-gated potassium (K ) channels are the largest superfamily of potassium (K) channels. A variety of K channels are expressed in the vascular smooth muscle cells (SMC). Studies have shown that gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) cause various changes in the human umbilical vein (HUV). Recently, we have shown that 4-AP, a nonspecific K 1-4 channel inhibitor, significantly decreases vasorelaxation induced by K channel opener pinacidil in vascular SMCs of the HUVs from normal pregnancies, but not in GDM and PIH. The goal of this study was to provide more detailed insight in the K channel subtypes involved in pinacidil-induced vasodilation of HUVs, as well as to investigate potential alterations of their function and expression during GDM and PIH. Margatoxin, a specific blocker of K 1.2 and K 1.3 channels, significantly antagonized pinacidil-induced vasorelaxation in normal pregnancy, while in HUVs from GDM and PIH that was not the case, indicating damage of K 1.2 and K 1.3 channel function. Immunohistochemistry and Western blot revealed similar expression of K 1.2 channels in all groups. The expression of K 1.3 subunit was significantly decreased in PIH, while it remained unchanged in GDM compared to normal pregnancy. Phrixotoxin, specific blocker of K 4.2 and K 4.3 channels, did not antagonize response to pinacidil in any of the groups. The major novel findings show that margatoxin antagonized pinacidil-induced relaxation in normal pregnancy, but not in GDM and PIH. Decreased expression of K 1.3 channels in HUV during PIH may be important pathophysiological mechanism contributing to an increased risk of adverse pregnancy outcomes.
T2  - European Journal of Pharmacology
T1  - Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle
VL  - 882
SP  - 173281
DO  - 10.1016/j.ejphar.2020.173281
ER  - 

@article{
author = "Đokić, Vladimir and Janković, Svetlana and Labudović-Borović, Milica and Rakočević, Jelena T. and Stanišić, Jelena and Rajković, Jovana and Novaković, Radmila and Kostić, Milan and Đurić, Miloš and Gostimirović, Miloš and Gojković-Bukarica, Ljiljana",
year = "2020",
abstract = "Voltage-gated potassium (K ) channels are the largest superfamily of potassium (K) channels. A variety of K channels are expressed in the vascular smooth muscle cells (SMC). Studies have shown that gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) cause various changes in the human umbilical vein (HUV). Recently, we have shown that 4-AP, a nonspecific K 1-4 channel inhibitor, significantly decreases vasorelaxation induced by K channel opener pinacidil in vascular SMCs of the HUVs from normal pregnancies, but not in GDM and PIH. The goal of this study was to provide more detailed insight in the K channel subtypes involved in pinacidil-induced vasodilation of HUVs, as well as to investigate potential alterations of their function and expression during GDM and PIH. Margatoxin, a specific blocker of K 1.2 and K 1.3 channels, significantly antagonized pinacidil-induced vasorelaxation in normal pregnancy, while in HUVs from GDM and PIH that was not the case, indicating damage of K 1.2 and K 1.3 channel function. Immunohistochemistry and Western blot revealed similar expression of K 1.2 channels in all groups. The expression of K 1.3 subunit was significantly decreased in PIH, while it remained unchanged in GDM compared to normal pregnancy. Phrixotoxin, specific blocker of K 4.2 and K 4.3 channels, did not antagonize response to pinacidil in any of the groups. The major novel findings show that margatoxin antagonized pinacidil-induced relaxation in normal pregnancy, but not in GDM and PIH. Decreased expression of K 1.3 channels in HUV during PIH may be important pathophysiological mechanism contributing to an increased risk of adverse pregnancy outcomes.",
journal = "European Journal of Pharmacology",
title = "Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle",
volume = "882",
pages = "173281",
doi = "10.1016/j.ejphar.2020.173281"
}

Đokić, V., Janković, S., Labudović-Borović, M., Rakočević, J. T., Stanišić, J., Rajković, J., Novaković, R., Kostić, M., Đurić, M., Gostimirović, M.,& Gojković-Bukarica, L.. (2020). Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle. in European Journal of Pharmacology, 882, 173281.
https://doi.org/10.1016/j.ejphar.2020.173281

Đokić V, Janković S, Labudović-Borović M, Rakočević JT, Stanišić J, Rajković J, Novaković R, Kostić M, Đurić M, Gostimirović M, Gojković-Bukarica L. Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle. in European Journal of Pharmacology. 2020;882:173281.
doi:10.1016/j.ejphar.2020.173281 .

Đokić, Vladimir, Janković, Svetlana, Labudović-Borović, Milica, Rakočević, Jelena T., Stanišić, Jelena, Rajković, Jovana, Novaković, Radmila, Kostić, Milan, Đurić, Miloš, Gostimirović, Miloš, Gojković-Bukarica, Ljiljana, "Pregnancy-induced hypertension decreases Kv1.3 potassium channel expression and function in human umbilical vein smooth muscle" in European Journal of Pharmacology, 882 (2020):173281,
https://doi.org/10.1016/j.ejphar.2020.173281 . .

TY  - JOUR
AU  - Đokić, Vladimir
AU  - Janković-Ražnatović, Svetlana
AU  - Novaković, Radmila
AU  - Kostić, Milan
AU  - Rajković, Jovana
AU  - Labudović-Borović, Milica
AU  - Rakočević, Jelena T.
AU  - Stanišić, Jelena
AU  - Đurić, Miloš
AU  - Gojković-Bukarica, Ljiljana
PY  - 2019
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/8626
AB  - Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) can jeopardize mother and/or fetus. Vascular ATP-sensitive potassium (KATP) channels most likely participate in the processes of diabetes and hypertension. The aim of this research was to examine whether GDM and PIH cause changes in the expression and function of KATP channels in vascular smooth muscle of human umbilical vein (HUV). Western blot and immunohistochemistry detected significantly decreased expression of Kir6.1 subunit of KATP channels in GDM and PIH, while the expression of SUR2B was unchanged. In GDM, a K+ channel opener, pinacidil caused reduced relaxation of the endothelium-denuded HUVs compared to normal pregnancy. However, its effects in HUVs from PIH subjects were similar to normal pregnancy. In all groups KATP channel blocker glibenclamide antagonized the relaxation of HUV induced by pinacidil without change in the maximal relaxations indicating additional KATP channel-independent mechanisms of pinacidil action. Iberiotoxin, a selective antagonist of large-conductance calcium-activated potassium channels, inhibited the relaxant effect of pinacidil in PIH, but not in normal pregnancy and GDM. Experiments performed in K+-rich solution confirmed the existence of K+-independent effects of pinacidil, which also appear to be impaired in GDM and PIH. Thus, the expression of KATP channels is decreased in GDM and PIH. In GDM, vasorelaxant response of HUV to pinacidil is reduced, while in PIH it remains unchanged. It is very likely that KATP channels modulation and more detailed insight in KATP channel-independent actions of pinacidil may be precious in the therapy of pathological pregnancies. © 2019 Elsevier Inc.
T2  - Experimental and Molecular Pathology
T1  - Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels
VL  - 111
SP  - 104323
DO  - 10.1016/j.yexmp.2019.104323
ER  - 

@article{
author = "Đokić, Vladimir and Janković-Ražnatović, Svetlana and Novaković, Radmila and Kostić, Milan and Rajković, Jovana and Labudović-Borović, Milica and Rakočević, Jelena T. and Stanišić, Jelena and Đurić, Miloš and Gojković-Bukarica, Ljiljana",
year = "2019",
abstract = "Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) can jeopardize mother and/or fetus. Vascular ATP-sensitive potassium (KATP) channels most likely participate in the processes of diabetes and hypertension. The aim of this research was to examine whether GDM and PIH cause changes in the expression and function of KATP channels in vascular smooth muscle of human umbilical vein (HUV). Western blot and immunohistochemistry detected significantly decreased expression of Kir6.1 subunit of KATP channels in GDM and PIH, while the expression of SUR2B was unchanged. In GDM, a K+ channel opener, pinacidil caused reduced relaxation of the endothelium-denuded HUVs compared to normal pregnancy. However, its effects in HUVs from PIH subjects were similar to normal pregnancy. In all groups KATP channel blocker glibenclamide antagonized the relaxation of HUV induced by pinacidil without change in the maximal relaxations indicating additional KATP channel-independent mechanisms of pinacidil action. Iberiotoxin, a selective antagonist of large-conductance calcium-activated potassium channels, inhibited the relaxant effect of pinacidil in PIH, but not in normal pregnancy and GDM. Experiments performed in K+-rich solution confirmed the existence of K+-independent effects of pinacidil, which also appear to be impaired in GDM and PIH. Thus, the expression of KATP channels is decreased in GDM and PIH. In GDM, vasorelaxant response of HUV to pinacidil is reduced, while in PIH it remains unchanged. It is very likely that KATP channels modulation and more detailed insight in KATP channel-independent actions of pinacidil may be precious in the therapy of pathological pregnancies. © 2019 Elsevier Inc.",
journal = "Experimental and Molecular Pathology",
title = "Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels",
volume = "111",
pages = "104323",
doi = "10.1016/j.yexmp.2019.104323"
}

Đokić, V., Janković-Ražnatović, S., Novaković, R., Kostić, M., Rajković, J., Labudović-Borović, M., Rakočević, J. T., Stanišić, J., Đurić, M.,& Gojković-Bukarica, L.. (2019). Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels. in Experimental and Molecular Pathology, 111, 104323.
https://doi.org/10.1016/j.yexmp.2019.104323

Đokić V, Janković-Ražnatović S, Novaković R, Kostić M, Rajković J, Labudović-Borović M, Rakočević JT, Stanišić J, Đurić M, Gojković-Bukarica L. Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels. in Experimental and Molecular Pathology. 2019;111:104323.
doi:10.1016/j.yexmp.2019.104323 .

Đokić, Vladimir, Janković-Ražnatović, Svetlana, Novaković, Radmila, Kostić, Milan, Rajković, Jovana, Labudović-Borović, Milica, Rakočević, Jelena T., Stanišić, Jelena, Đurić, Miloš, Gojković-Bukarica, Ljiljana, "Effect of gestational diabetes mellitus and pregnancy-induced hypertension on human umbilical vein smooth muscle KATP channels" in Experimental and Molecular Pathology, 111 (2019):104323,
https://doi.org/10.1016/j.yexmp.2019.104323 . .