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Mahapatra C, Thakkar R, Kumar R. Modulatory Impact of Oxidative Stress on Action Potentials in Pathophysiological States: A Comprehensive Review. Antioxidants (Basel) 2024; 13:1172. [PMID: 39456426 PMCID: PMC11504047 DOI: 10.3390/antiox13101172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/12/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses, significantly affects cellular function and viability. It plays a pivotal role in modulating membrane potentials, particularly action potentials (APs), essential for properly functioning excitable cells such as neurons, smooth muscles, pancreatic beta cells, and myocytes. The interaction between oxidative stress and AP dynamics is crucial for understanding the pathophysiology of various conditions, including neurodegenerative diseases, cardiac arrhythmias, and ischemia-reperfusion injuries. This review explores how oxidative stress influences APs, focusing on alterations in ion channel biophysics, gap junction, calcium dynamics, mitochondria, and Interstitial Cells of Cajal functions. By integrating current research, we aim to elucidate how oxidative stress contributes to disease progression and discuss potential therapeutic interventions targeting this interaction.
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Affiliation(s)
- Chitaranjan Mahapatra
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA
| | - Ravindra Thakkar
- California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA
| | - Ravinder Kumar
- Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Liu Y, Cheng Y, Xiang N, Wang Z, Li S, Gong L, Wang X. Aerobic exercise improves BK Ca channel-mediated vasodilation in diabetic vascular smooth muscle via AMPK/Nrf2/HO-1 pathway. Acta Diabetol 2024; 61:425-434. [PMID: 38041787 DOI: 10.1007/s00592-023-02210-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 11/07/2023] [Indexed: 12/03/2023]
Abstract
AIMS This study aims to investigate the effect of aerobic exercise training on BKCa channel in diabetic vascular smooth muscle and explore the underlying mechanism. METHODS Control m/m mice and diabetic db/db mice were randomly assigned to sedentary groups (W and D) and exercise training groups (WE and DE). Mice in exercise groups underwent training sessions lasting for 12 weeks, with a speed of 12 m/min for 60 min, five times per week. The thoracic aorta was extracted isolated and examined for measurement of vascular structure, global levels of reactive oxygen species (ROS), vasodilation, and protein expression. Rat thoracic aorta vascular smooth muscle cells (USMCs) were cultured, and siRNA transfection was conducted to detect whether AMPK contributed to the regulation. ROS level and protein expression were measured. RESULTS Compared with control mice, diabetic mice had a larger vascular medium thickness, impaired BKCa-mediated vasodilation, a higher level of ROS, and a lower expression of BKCa α, BKCa β1, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. Exercise training increased the expression of BKCa α, Nrf2, p-Nrf2, p-Nrf2/Nrf2, HO-1, and p-AMPK/AMPK. AMPK deletion led to lower ROS levels and expression of BKCa α, β1, Nrf2, and HO-1 in USMCs cultured in high glucose conditions. CONCLUSIONS BKCa channel protein expression reduction in VSMCs contributes to vasodilation and vascular remodeling dysfunction in diabetes mellitus. Aerobic exercise can promote the expression of BKCa channel and improve BKCa-mediated vascular dysfunction in diabetic VSMCs through AMPK/Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Yujia Liu
- Department of Physical Education, Jiangsu Normal University, Xuzhou, China
| | - Yue Cheng
- Department of Physical Education, Jiangsu Normal University, Xuzhou, China
| | - Na Xiang
- Caoxian People's Hospital, Heze, China
| | - Zhiyuan Wang
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
| | - Siyu Li
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
| | - Lijing Gong
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
| | - Xingqi Wang
- Biomedical R&d Center, School of Life Science, Jiangsu Normal University, Tongshan District, No. 101, Shanghai Road, Xuzhou, Jiangsu, China.
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Niloy SI, Shen Y, Guo L, O’Rourke ST, Sun C. Loss of IP3R-BK Ca Coupling Is Involved in Vascular Remodeling in Spontaneously Hypertensive Rats. Int J Mol Sci 2023; 24:10903. [PMID: 37446080 PMCID: PMC10341547 DOI: 10.3390/ijms241310903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Mechanisms by which BKCa (large-conductance calcium-sensitive potassium) channels are involved in vascular remodeling in hypertension are not fully understood. Vascular smooth muscle cell (VSMC) proliferation and vascular morphology were compared between hypertensive and normotensive rats. BKCa channel activity, protein expression, and interaction with IP3R (inositol 1,4,5-trisphosphate receptor) were examined using patch clamp, Western blot analysis, and coimmunoprecipitation. On inside-out patches of VSMCs, the Ca2+-sensitivity and voltage-dependence of BKCa channels were similar between hypertensive and normotensive rats. In whole-cell patch clamp configuration, treatment of cells with the IP3R agonist, Adenophostin A (AdA), significantly increased BKCa channel currents in VSMCs of both strains of rats, suggesting IP3R-BKCa coupling; however, the AdA-induced increases in BKCa currents were attenuated in VSMCs of hypertensive rats, indicating possible IP3R-BKCa decoupling, causing BKCa dysfunction. Co-immunoprecipitation and Western blot analysis demonstrated that BKCa and IP3R proteins were associated together in VSMCs; however, the association of BKCa and IP3R proteins was dramatically reduced in VSMCs of hypertensive rats. Genetic disruption of IP3R-BKCa coupling using junctophilin-2 shRNA dramatically augmented Ang II-induced proliferation in VSMCs of normotensive rats. Subcutaneous infusion of NS1619, a BKCa opener, to reverse BKCa dysfunction caused by IP3R-BKCa decoupling significantly attenuated vascular hypertrophy in hypertensive rats. In summary, the data from this study demonstrate that loss of IP3R-BKCa coupling in VSMCs induces BKCa channel dysfunction, enhances VSMC proliferation, and thus, may contribute to vascular hypertrophy in hypertension.
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Affiliation(s)
- Sayeman Islam Niloy
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA (Y.S.); (S.T.O.)
| | - Yue Shen
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA (Y.S.); (S.T.O.)
| | - Lirong Guo
- School of Nursing, Jilin University, Changchun 130021, China;
| | - Stephen T. O’Rourke
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA (Y.S.); (S.T.O.)
| | - Chengwen Sun
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA (Y.S.); (S.T.O.)
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Martins DRDS, Lescano CH, Justo AFO, Vicente JM, Santos SHS, Aguilar CM, Borges A, Pires de Oliveira I, Sanjinez-Argandoña EJ. Effect of Different Extraction Methods on Anthocyanin Content in Hibiscus sabdariffa L. and their Antiplatelet and Vasorelaxant Properties. PLANT FOODS FOR HUMAN NUTRITION (DORDRECHT, NETHERLANDS) 2023:10.1007/s11130-023-01067-5. [PMID: 37120677 DOI: 10.1007/s11130-023-01067-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 06/19/2023]
Abstract
Hibiscus sabdariffa L. is a worldwide component for tea and beverages, being a natural source of anthocyanins, which are associated with cardiovascular activities. To investigate this relationship, we explored different methods of aqueous extraction on the anthocyanin content and antioxidant activity of H. sabdariffa L. calyx extract (HSCE). Pharmacological effects via platelet aggregation, calcium mobilization, cyclic nucleotide levels, vasodilator-stimulated phosphoprotein Ser157 and Ser239, and on the vasomotor response of aortic rings isolated from mice are studied herewith. We found that the application of ultrasonic turbolization, 20 min, combined with acidified water was significantly more effective in the extraction process, providing extracts with the highest levels of anthocyanins (8.73 and 9.63 mg/100 g) and higher antioxidant activity (6.66 and 6.78 μM trolox/g of sample). HSCE significantly inhibited (100-1000 μg/mL) arachidonic acid-induced platelet aggregation, reduced calcium mobilization, and increased cAMP and cGMP levels with VASPSer157 and VASPSer239 phosphorylation. Vasorelaxation reduction was confirmed by the aortic rings and endothelium assays treated with nitric oxide synthase inhibitors, soluble guanylyl cyclase (sGC) oxidizing agent, or Ca2+-activated K+ channel inhibitor. The increasing of cGMP levels could be understood considering the sGC stimulation by HSCE compounds in the specific stimulus domain, which allows an understanding of the observed antiplatelet and vasorelaxant properties of H. sabdariffa L. calyx extract.
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Affiliation(s)
| | - Caroline Honaiser Lescano
- Department of Pharmacology, University of Campinas, Campinas, SP, 13083-881, Brazil
- Institute of Agricultural Sciences, Federal University of Minas Gerais, Montes Claros, MG, 39404-547, Brazil
| | - Alberto Fernando Oliveira Justo
- Department of Pharmacology, University of Campinas, Campinas, SP, 13083-881, Brazil
- Department of Internal Medicine, University of São Paulo Medical School, São Paulo, SP, Brazil
| | | | | | - Charles Martins Aguilar
- Institute of Agricultural Sciences, Federal University of Minas Gerais, Montes Claros, MG, 39404-547, Brazil
| | - Alexandre Borges
- Faculty of Medicine, UNIFUNEC University Center, Santa Fé do Sul, SP, 15775-000, Brazil
| | - Ivan Pires de Oliveira
- Institute of Agricultural Sciences, Federal University of Minas Gerais, Montes Claros, MG, 39404-547, Brazil.
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Lin YK, Chen YJ, Li JY, Chen YL, He D, Zuo R, Xiao MJ, Xu DP, Zheng CY, Wang W, He RR, Chen Y. Salvianolic acid A from Danhong Injection induces vasorelaxation by Regulating L-type calcium channel in isolated mouse arteries. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115431. [PMID: 35700852 DOI: 10.1016/j.jep.2022.115431] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Danhong injection (DHI), which is a Chinese clinical prescription consists of Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Honghua in Chinese)(Plant names have been checked with http://www.theplantlist.org on March 1st, 2022), has been mainly used in the clinical therapy of cardiovascular diseases, including hypertension in China for many years. AIM OF THE STUDY Cardiovascular diseases (CVDs) are the major causes of death all around the world. Due to the various stimulation, a series of vasoconstrictor substances are secreted to regulate the vasoconstriction function and then change blood pressure. The representative substances leading to abnormal vasoconstriction include renin-angiotensin system, endothelin, vasopressin and adrenaline, which act on the corresponding receptors on vascular smooth muscle to constrict blood vessels. Finally, blood pressure increases, followed by a series of cardiovascular diseases, including hypertension. However, little is known about Danhong injection's specific vasodilating mechanisms and active substances. The aims of the study were to determine the vasodilating substances of Danhong injection and explain its molecular mechanism of vasodilation. MATERIALS AND METHODS The effects of DHI and its active components on vascular tension were measured by myograph system in the aortic or mesenteric rings of mice. Based on this, the pharmacodynamic substances were analyzed and effective molecules were found. Combined with multiple types of vascular myograph experiments and network pharmacological analysis, the molecular pathway was preliminarily determined. With molecular biology experiments, it was verified that the relevant mechanisms were closely related to calcium-mediated vasoconstriction in smooth muscle cells. RESULTS DHI could relax endothelium-removed aortic rings pre-constricted with PE and 3 possible active vasodilator substances, including salvianolic acid A, salvianolic acid B and danshensu, were screened out by network pharmacology and vascular myograph experiments, among which the effects of salvianolic acid A were dominant. Meanwhile, salvianolic acid A could dilate mesenteric artery in a pressure-dependent manner. Interestingly, salvianolic acid A could still relax the vascular rings under the stimulation of KCl and Bayk8644, two agonists of L-type calcium channel. By contrast, inhibitors of Kir, Kv, Katp and BKCa channels did not block the effect of salvianolic acid A on vasodilation. Salvianolic acid A alleviated Ca2+ transient, referring to changes of intracellular calcium, induced by PE, Bayk8644 and high K+ in the VSMCs. Salvianolic acid A could partially restore the vasodilation function of vascular smooth muscle damaged by AngII and ET-1 induced hypertension situation. CONCLUSIONS Our results indicate that salvianolic acid A is the major vasodilator substance in DHI and the vasorelaxation pharmacology mechanism involved in inhibiting the L-type calcium channel signaling in smooth muscle cell. Hence, there are potential therapeutic effects of taking salvianolic acid A preparation which may be beneficial to protect cardiovascular system and reduce blood pressure.
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Affiliation(s)
- Yi-Ke Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Yi-Jun Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Jie-Yi Li
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Yu-Lin Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Dong He
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Rui Zuo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Min-Jun Xiao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Dan-Ping Xu
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China.
| | - Chao-Yang Zheng
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510020, China.
| | - Wei Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
| | - Rong-Rong He
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China.
| | - Yang Chen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
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Activating BK channels ameliorates vascular smooth muscle calcification through Akt signaling. Acta Pharmacol Sin 2022; 43:624-633. [PMID: 34163023 PMCID: PMC8888620 DOI: 10.1038/s41401-021-00704-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/23/2021] [Indexed: 02/06/2023]
Abstract
Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by β-glycerophosphate (β-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in β-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In β-GP-treated VSMCs, BK channel opener NS1619 (20 μM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 μM) caused the opposite effects. In primary cultured VSMCs from BK-/- mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK-/- mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg-1 ·d-1) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 μM) or FoxO1 inhibitor AS1842856 (3 μM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.
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Wang LF, Ling DY, Huang MX, Tao LW, Tong QX, Hou Y, Li H, Chen Z, Zhang BZ, Lu HT, Wang YF, Zhang XG. Influence of atherosclerosis on the molecular expression of the TRPC1/BK signal complex in the aortic smooth muscles of mice. Exp Ther Med 2022; 23:4. [PMID: 34815756 PMCID: PMC8593874 DOI: 10.3892/etm.2021.10926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/08/2021] [Indexed: 11/30/2022] Open
Abstract
Atherosclerosis (AS) is one a disease that seriously endangers human health. Previous studies have demonstrated that transient receptor potential channel-1 (TRPC1)/large conductance Ca2+ activated K+ channel (BK) signal complex is widely distributed in arteries. Therefore, it was hypothesized that TRPC1-BK signal complex may be a new target for the treatment of AS-related diseases. Apolipoprotein E-/- (ApoE-/-) mice were used to establish an atherosclerotic animal model in the present study, and the association between AS and the TRPC1-BK signal complex was examined. The present study aimed to compare the differences in the expression levels of mRNAs and proteins of the TRPC1-BK signal complex expressed in the aortic vascular smooth muscle tissue, between mice with AS and control mice. There were 10 mice in each group. Reverse transcription PCR, western blotting and immunohistochemistry were used to detect the differences in the mRNA and protein expression levels of TRPC1, BKα (the α subunit of BK) and BKβ1 (the β1 subunit of BK). The mRNA expression level of TRPC1 in AS model mice was significantly higher compared with that in the control group (P<0.05). However, the mRNA expression levels of BKα and BKβ1 were lower compared with those in the controls (both P<0.01). The mice in the ApoE-/- group successfully developed AS. In this group, the protein expression level of TRPC1 was significantly higher than that in the control group (P<0.01), while the protein expression levels of BKα and BKβ1 were lower compared with those in the control group (P<0.01 and P<0.05, respectively). Collectively, it was identified that the protein and mRNA expression levels of the TRPC1/BK signal complex in the aortic vascular smooth muscle tissue could be influenced by the development of AS in mice. Hence, the TRPC1/BK signal complex may be a potential therapeutic target for the prevention and treatment of AS-related complications in the future.
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Affiliation(s)
- Lian-Fa Wang
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Dong-Yun Ling
- Department of Cardiology, The Second People's Hospital of Hefei City, Hefei, Anhui 230011, P.R. China
| | - Meng-Xun Huang
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Li-Wei Tao
- Department of Cardiothoracic Surgery, The Second People's Hospital of Fuyang City, Fuyang, Anhui 236000, P.R. China
| | - Quan-Xiu Tong
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Yong Hou
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Hua Li
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Zhen Chen
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Bang-Zhu Zhang
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Hong-Tao Lu
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Yun-Fei Wang
- Department of Cardiology, The 901st Hospital of Joint Logistics Support Force of PLA, Hefei, Anhui 230031, P.R. China
| | - Xian-Ge Zhang
- Institute of Public Health and Nursing Research, Department of Healthcare Management, University of Bremen, 28359 Bremen, Germany
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Li H, An JR, Seo MS, Kang M, Heo R, Park S, Mun SY, Bae YM, Han ET, Han JH, Chun W, Na SH, Park WS. Downregulation of large-conductance Ca 2+-activated K + channels in human umbilical arterial smooth muscle cells in gestational diabetes mellitus. Life Sci 2022; 288:120169. [PMID: 34822796 DOI: 10.1016/j.lfs.2021.120169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 11/25/2022]
Abstract
AIMS We investigated the changes in large-conductance Ca2+-activated K+ (BKCa) channels from human umbilical arterial smooth muscle cells experiencing gestational diabetes mellitus (GDM). MAIN METHODS Whole-cell patch-clamp technique, arterial tone measurement, RT-PCR, Quantitative real-time PCR, western blot were performed in human umbilical arterial smooth muscle cells. KEY FINDINGS Whole-cell BKCa current density was decreased in the GDM group compared with the normal group. The vasorelaxant effects of the synthetic BKCa channel activator NS-1619 (10 μM) were impaired in the GDM group compared with the normal group. Reverse-transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and western blot analyses suggested that the mRNA, total RNA, and protein expression levels of the BKCa channel were decreased in the GDM group relative to the normal group. In addition, the expression levels of protein kinase A and protein kinase G, which regulate BKCa channel activity, remained unchanged between the groups. Applying the BKCa channel inhibitor paxilline (10 μM) induced vasoconstriction and membrane depolarization of isolated umbilical arteries in the normal group but showed less of an effect on umbilical arteries in the GDM group. SIGNIFICANCE Our results demonstrate for the first time impaired BKCa current and BKCa channel-induced vasorelaxation activities that were not caused by impaired BKCa channel-regulated protein kinases, but by decreased expression of the BKCa channels, in the umbilical arteries of GDM patients.
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Affiliation(s)
- Hongliang Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, Jiangsu, China
| | - Jin Ryeol An
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Mi Seon Seo
- Department of Physiology, Konkuk University School of Medicine, Chungju 27478, South Korea
| | - Minji Kang
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Ryeon Heo
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Seojin Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Seo-Yeong Mun
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Young Min Bae
- Department of Physiology, Konkuk University School of Medicine, Chungju 27478, South Korea
| | - Eun-Taek Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Jin-Hee Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea
| | - Sung Hun Na
- Institute of Medical Sciences, Department of Obstetrics and Gynecology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon 24341, South Korea.
| | - Won Sun Park
- Institute of Medical Sciences, Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, South Korea.
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García-Carlos CA, Camargo-Loaiza JA, García-Villa D, López-Cervantes JG, Domínguez-Avila JA, González-Aguilar GA, Astiazaran-Garcia H, Montiel-Herrera M. Angiotensin II, ATP and high extracellular potassium induced intracellular calcium responses in primary rat brain endothelial cell cultures. Cell Biochem Funct 2021; 39:688-698. [PMID: 33821520 DOI: 10.1002/cbf.3635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/16/2021] [Accepted: 03/23/2021] [Indexed: 01/02/2023]
Abstract
The meninges shield the nervous system from diverse, rather harmful stimuli and pathogens from the periphery. This tissue is composed of brain endothelial cells (BECs) that express diverse ion channels and chemical-transmitter receptors also expressed by neurons and glial cells to communicate with each other. However, information about the effects of ATP and angiotensin II on BECs is scarce, despite their essential roles in blood physiology. This work investigated in vitro if BECs from the meninges from rat forebrain respond to ATP, angiotensin II and high extracellular potassium, with intracellular calcium mobilizations and its second messenger-associated pathways. We found that in primary BEC cultures, both ATP and angiotensin II produced intracellular calcium responses linked to the activation of inositol trisphosphate receptors and ryanodine receptors, which led to calcium release from intracellular stores. We also used RT-PCR to explore what potassium channel subunits are expressed by primary BEC cultures and freshly isolated meningeal tissue, and which might be linked to the observed effects. We found that BECs mainly expressed the inward rectifier potassium channel subunits Kir1.1, Kir3.3, Kir 4.1 and Kir6.2. This study contributes to the understanding of the functions elicited by ATP and angiotensin II in BECs from rat meninges. SIGNIFICANCE OF THE STUDY: Brain endothelial cells (BECs) express diverse ion channels and membrane receptors, which they might use to communicate with neurons and glia. This work investigated in vitro, if BECs from the rat forebrain respond to angiotensin II and ATP with intracellular calcium mobilizations. We found that these cells did respond to said substances with intracellular calcium mobilizations linked to inositol trisphosphate and ryanodine receptor activation, which led to calcium release from intracellular stores. These findings are important because they might uncover routes of active communication between brain cells and endothelial cells.
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Affiliation(s)
| | | | - Denisse García-Villa
- Departamento de Medicina y Ciencias de la Salud, Universidad de Sonora, Hermosillo, Sonora, Mexico
| | | | - J Abraham Domínguez-Avila
- Cátedras CONACYT-Centro de Investigación en Alimentación y Desarrollo A.C., Hermosillo, Sonora, Mexico
| | - Gustavo A González-Aguilar
- Laboratorio de Antioxidantes y Alimentos Funcinales, Centro de Investigación en Alimentación y Desarrollo A.C., Hermosillo, Sonora, Mexico
| | - Humberto Astiazaran-Garcia
- Laboratorio de Patología Experimental, Centro de Investigación en Alimentación y Desarrollo A.C., Hermosillo, Sonora, Mexico
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10
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Zhang R, Ma WQ, Fu MJ, Li J, Hu CH, Chen Y, Zhou MM, Gao ZJ, He YL. Overview of bile acid signaling in the cardiovascular system. World J Clin Cases 2021; 9:308-320. [PMID: 33521099 PMCID: PMC7812903 DOI: 10.12998/wjcc.v9.i2.308] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.
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Affiliation(s)
- Rou Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Wen-Qi Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Jun Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chun-Hua Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Mi-Mi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhi-Jie Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Li He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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11
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Liu G, Fu D, Tian H, Dai A. The mechanism of ions in pulmonary hypertension. Pulm Circ 2021; 11:2045894020987948. [PMID: 33614016 PMCID: PMC7869166 DOI: 10.1177/2045894020987948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/23/2020] [Indexed: 12/15/2022] Open
Abstract
Pulmonary hypertension(PH)is a kind of hemodynamic and pathophysiological state, in which the pulmonary artery pressure (PAP) rises above a certain threshold. The main pathological manifestation is pulmonary vasoconstriction and remodelling progressively. More and more studies have found that ions play a major role in the pathogenesis of PH. Many vasoactive substances, inflammatory mediators, transcription-inducing factors, apoptosis mediators, redox substances and translation modifiers can control the concentration of ions inside and outside the cell by regulating the activity of ion channels, which can regulate vascular contraction, cell proliferation, migration, apoptosis, inflammation and other functions. We all know that there are no effective drugs to treat PH. Ions are involved in the occurrence and development of PH, so it is necessary to clarify the mechanism of ions in PH as a therapeutic target for PH. The main ions involved in PH are calcium ion (Ca2+), potassium ion (K+), sodium ion (Na+) and chloride ion (Cl-). Here, we mainly discuss the distribution of these ions and their channels in pulmonary arteries and their role in the pathogenesis of PH.
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Affiliation(s)
- Guogu Liu
- Department of Graduate School, University of South China,
Hengyang, China
- Department of Respiratory Medicine, Hunan Provincial People’s
Hospital, Changsha, China
| | - Daiyan Fu
- Department of Respiratory Medicine, Hunan Provincial People’s
Hospital, Changsha, China
| | - Heshen Tian
- Department of Graduate School, University of South China,
Hengyang, China
- Department of Respiratory Medicine, Hunan Provincial People’s
Hospital, Changsha, China
| | - Aiguo Dai
- Department of Respiratory Diseases, Hunan University of Chinese
Medicine, Changsha, China
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12
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Abstract
Aberrant function or expression of potassium channels can be underlying in pathologies such as cardiac arrhythmia, diabetes mellitus, hypertension, preterm birth, and various types of cancer. The expression of potassium channels is altered in many types of diseases. Also, we have previously shown that natural polyphenols, such as resveratrol, and selective synthetic modulators of potassium channels, like pinacidil, can alter their function and lead to the desired outcome. Therefore, targeting potassium channels with substance, which has an influence on their function, is promising access to cancer, diabetes mellitus, preterm birth, or hypertension therapy. In this chapter, we could discuss strategies for targeting different types of potassium channels as potential targets for synthetic and natural molecules therapy.
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13
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Zhang F, Feng J, Zhang J, Kang X, Qian D. Quercetin modulates AMPK/SIRT1/NF-κB signaling to inhibit inflammatory/oxidative stress responses in diabetic high fat diet-induced atherosclerosis in the rat carotid artery. Exp Ther Med 2020; 20:280. [PMID: 33200005 DOI: 10.3892/etm.2020.9410] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/14/2020] [Indexed: 12/21/2022] Open
Abstract
Inflammation and oxidative stress serve interrelated roles in the development of atherosclerosis and other vascular diseases. Quercetin has been previously reported to exhibit numerous beneficial properties towards several metabolic conditions and cardiovascular disease. The present study aimed to evaluate the effects of quercetin on the 5'adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/NF-κB signaling pathway and inflammatory/oxidative stress response in diabetic-induced atherosclerosis in the carotid artery of rats. Male Wistar rats were used to create a diabetes-induced atherosclerosis model by the administration of high fat diet (HFD) with streptozotocin, which lasted for 8 weeks. Control and diabetic rats received quercetin (30 mg/kg/day; orally) for the last 2 weeks of the diabetic period. Plasma lipid profile and vascular levels of oxidative stress markers, inflammatory cytokines, NF-κB signaling proteins and SIRT1 expression were evaluated using ELISA and western blotting. Quercetin treatment in HFD diabetic rats was reported to improve the lipid profile and reduce the number of atherosclerotic lesions, atherogenic index and malondialdehyde levels, whilst increasing the activity of enzymatic antioxidants in the carotid artery. Additionally, the inflammatory response was suppressed by quercetin administration, as indicated by the reduced NF-κB and IL-1β levels, and increased IL-10 levels. Furthermore, SIRT1 expression was revealed to be significantly increased in response to quercetin treatment compared with non-treated HFD rats. However, these effects of quercetin were abolished or reversed by the administration of compound-C (0.2 mg/kg), a specific AMPK blocker, in HFD rats. Therefore, quercetin may have promising potential in ameliorating atherosclerotic pathophysiology in the rat carotid artery by inhibiting oxidative stress and inflammatory responses mechanistically by modulating the AMPK/SIRT1/NF-κB signaling pathway.
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Affiliation(s)
- Fengwei Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710038, P.R. China
| | - Jia Feng
- Department of Endocrinology, Ninth Hospital of Xi'an, Xi'an, Shaanxi 710054, P.R. China
| | - Jingyu Zhang
- Department of Gastroenterology, Tangdu Hospital, Air Force Military Medical University, Xi'an, Shaanxi 710082, P.R. China
| | - Xin Kang
- Department of Endocrinology, Xi'an International Medical Center Hospital, Xi'an, Shaanxi 710100, P.R. China
| | - Dun Qian
- Department of Cardiology, Xi'an Lintong Development Zone Boren Hospital, Xi'an, Shaanxi 710600, P.R. China
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14
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Deng M, Su D, Xu S, Little PJ, Feng X, Tang L, Shen A. Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function. Front Pharmacol 2020; 11:635. [PMID: 32457625 PMCID: PMC7227439 DOI: 10.3389/fphar.2020.00635] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/21/2020] [Indexed: 12/16/2022] Open
Abstract
Metformin has been used in diabetes for more than 60 years and has excellent safety in the therapy of human type 2 diabetes (T2D). There is growing evidence that the beneficial health effects of metformin are beyond its ability to improve glucose metabolism. Metformin not only reduces the incidence of cardiovascular diseases (CVD) in T2D patients, but also reduces the burden of atherosclerosis (AS) in pre-diabetes patients. Vascular smooth muscle cells (VSMCs) function is an important factor in determining the characteristics of the entire arterial vessel. Its excessive proliferation contributes to the etiology of several types of CVD, including AS, restenosis, and pulmonary hypertension. Current studies show that metformin has a beneficial effect on VSMCs function. Therefore, this review provides a timely overview of the role and molecular mechanisms by which metformin acts through VSMCs to protect CVD.
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Affiliation(s)
- Mingying Deng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Dan Su
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Suowen Xu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peter J Little
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.,Department of Pharmacy, Xinhua College of Sun Yat-sen University, Guangzhou, China
| | - Xiaojun Feng
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Liqin Tang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Aizong Shen
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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15
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Zhu Y, Jiang X, Ye P, Wang Z, Zheng Y, Liu Z, Chen S, Zhang D. Knockout of AKAP150 improves impaired BK channel-mediated vascular dysfunction through the Akt/GSK3β signalling pathway in diabetes mellitus. J Cell Mol Med 2020; 24:4716-4725. [PMID: 32163656 PMCID: PMC7176888 DOI: 10.1111/jcmm.15143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 02/05/2020] [Accepted: 02/19/2020] [Indexed: 12/15/2022] Open
Abstract
Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3β signalling contributed to decreased BK-β1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-β1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-β1 expression, and treatment with AKAP150 siRNA suppressed GSK3β expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3β signalling pathway in diabetes mellitus.
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Affiliation(s)
- Yan‐Rong Zhu
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Xiao‐Xin Jiang
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Peng Ye
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Zhi‐Mei Wang
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Yaguo Zheng
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Zhizhong Liu
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Shao‐Liang Chen
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Dai‐Min Zhang
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityNanjingChina
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16
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Zhu YR, Jiang XX, Zhang DM. Critical regulation of atherosclerosis by the KCa3.1 channel and the retargeting of this therapeutic target in in-stent neoatherosclerosis. J Mol Med (Berl) 2019; 97:1219-1229. [DOI: 10.1007/s00109-019-01814-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 05/07/2019] [Accepted: 06/18/2019] [Indexed: 01/09/2023]
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17
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Zhou ZY, Zhao WR, Zhang J, Chen XL, Tang JY. Sodium tanshinone IIA sulfonate: A review of pharmacological activity and pharmacokinetics. Biomed Pharmacother 2019; 118:109362. [PMID: 31545252 DOI: 10.1016/j.biopha.2019.109362] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/06/2019] [Accepted: 08/14/2019] [Indexed: 02/08/2023] Open
Abstract
Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivate of tanshinone IIA (Tan IIA) which is an active lipophilic constitute of Chinese Materia Medica Salvia miltiorrhiza Bge. (Danshen). STS presents multiple pharmacological activities, including anti-oxidant, anti-inflammation and anti-apoptosis, and has been approved for treatment of cardiovascular diseases by China State Food and Drug Administration (CFDA). In this review, we comprehensively summarized the pharmacological activities and pharmacokinetics of STS, which could support the further application and development of STS. In the recent decades, numerous experimental and clinical studies have been conducted to investigate the potential treatment effects of STS in various diseases, such as heart diseases, brain diseases, pulmonary diseases, cancers, sepsis and so on. The underlying mechanisms were most related to anti-oxidative and anti-inflammatory effects of STS via regulating various transcription factors, such as NF-κB, Nrf2, Stat1/3, Smad2/3, Hif-1α and β-catenin. Iron channels, including Ca2+, K+ and Cl- channels, were also the important targets of STS. Additionally, we emphasized the differences between STS and Tan IIA despite the interchangeable use of Tan IIA and STS in many previous studies. It is promising to improve the efficacy and reduce side effects of chemotherapeutic drug by the combination use of STS in canner treatment. The application of STS in pregnancy needs to be seriously considered. Moreover, the drug-drug interactions between STS and other drugs needs to be further studied as well as the complications of STS.
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Affiliation(s)
- Zhong-Yan Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
| | - Wai-Rong Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Cardiac Rehabilitation Center of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jing Zhang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Xin-Lin Chen
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Jing-Yi Tang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Cardiac Rehabilitation Center of Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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18
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Dogan MF, Yildiz O, Arslan SO, Ulusoy KG. Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective. Fundam Clin Pharmacol 2019; 33:504-523. [PMID: 30851197 DOI: 10.1111/fcp.12461] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 02/28/2019] [Accepted: 03/07/2019] [Indexed: 12/23/2022]
Abstract
Potassium (K+ ) ion channel activity is an important determinant of vascular tone by regulating cell membrane potential (MP). Activation of K+ channels leads to membrane hyperpolarization and subsequently vasodilatation, while inhibition of the channels causes membrane depolarization and then vasoconstriction. So far five distinct types of K+ channels have been identified in vascular smooth muscle cells (VSMCs): Ca+2 -activated K+ channels (BKC a ), voltage-dependent K+ channels (KV ), ATP-sensitive K+ channels (KATP ), inward rectifier K+ channels (Kir ), and tandem two-pore K+ channels (K2 P). The activity and expression of vascular K+ channels are changed during major vascular diseases such as hypertension, pulmonary hypertension, hypercholesterolemia, atherosclerosis, and diabetes mellitus. The defective function of K+ channels is commonly associated with impaired vascular responses and is likely to become as a result of changes in K+ channels during vascular diseases. Increased K+ channel function and expression may also help to compensate for increased abnormal vascular tone. There are many pharmacological and genotypic studies which were carried out on the subtypes of K+ channels expressed in variable amounts in different vascular beds. Modulation of K+ channel activity by molecular approaches and selective drug development may be a novel treatment modality for vascular dysfunction in the future. This review presents the basic properties, physiological functions, pathophysiological, and pharmacological roles of the five major classes of K+ channels that have been determined in VSMCs.
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Affiliation(s)
- Muhammed Fatih Dogan
- Department of Pharmacology, Ankara Yildirim Beyazit University, Bilkent, Ankara, 06010, Turkey
| | - Oguzhan Yildiz
- Department of Pharmacology, Gulhane Faculty of Medicine, University of Health Sciences, Etlik, Ankara, 06170, Turkey
| | - Seyfullah Oktay Arslan
- Department of Pharmacology, Ankara Yildirim Beyazit University, Bilkent, Ankara, 06010, Turkey
| | - Kemal Gokhan Ulusoy
- Department of Pharmacology, Gulhane Faculty of Medicine, University of Health Sciences, Etlik, Ankara, 06170, Turkey
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19
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Ye P, Zhu Y, Gu Y, Zhang D, Chen S. Functional protection against cardiac diseases depends on ATP-sensitive potassium channels. J Cell Mol Med 2018; 22:5801-5806. [PMID: 30596400 PMCID: PMC6237599 DOI: 10.1111/jcmm.13893] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 08/12/2018] [Indexed: 12/20/2022] Open
Abstract
ATP-sensitive potassium channels (KATP) channels are widely distributed in various tissues, including pancreatic beta cells, muscle tissue and brain tissue. KATP channels play an important role in cardioprotection in physiological/pathological situations. KATP channels are inhibited by an increase in the intracellular ATP concentration and are stimulated by an increase in the intracellular MgADP concentration. Activation of KATP channels decreases ischaemia/reperfusion injury, protects cardiomyocytes from heart failure, and reduces the occurrence of arrhythmias. KATP channels are involved in various signalling pathways, and their participation in protective processes is regulated by endogenous signalling molecules, such as nitric oxide and hydrogen sulphide. KATP channels may act as a new drug target to fight against cardiovascular disease in the development of related drugs in the future. This review highlights the potential mechanisms correlated with the protective role of KATP channels and their therapeutic value in cardiovascular diseases.
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Affiliation(s)
- Peng Ye
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityJiangsuChina
| | - Yan‐Rong Zhu
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityJiangsuChina
| | - Yue Gu
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityJiangsuChina
| | - Dai‐Min Zhang
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityJiangsuChina
| | - Shao‐Liang Chen
- Department of CardiologyNanjing First HospitalNanjing Medical UniversityJiangsuChina
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20
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Dopico AM, Bukiya AN, Jaggar JH. Calcium- and voltage-gated BK channels in vascular smooth muscle. Pflugers Arch 2018; 470:1271-1289. [PMID: 29748711 DOI: 10.1007/s00424-018-2151-y] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 04/27/2018] [Indexed: 02/04/2023]
Abstract
Ion channels in vascular smooth muscle regulate myogenic tone and vessel contractility. In particular, activation of calcium- and voltage-gated potassium channels of large conductance (BK channels) results in outward current that shifts the membrane potential toward more negative values, triggering a negative feed-back loop on depolarization-induced calcium influx and SM contraction. In this short review, we first present the molecular basis of vascular smooth muscle BK channels and the role of subunit composition and trafficking in the regulation of myogenic tone and vascular contractility. BK channel modulation by endogenous signaling molecules, and paracrine and endocrine mediators follows. Lastly, we describe the functional changes in smooth muscle BK channels that contribute to, or are triggered by, common physiological conditions and pathologies, including obesity, diabetes, and systemic hypertension.
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Affiliation(s)
- Alex M Dopico
- Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, 71 South Manassas St., Memphis, TN, 38163, USA.
| | - Anna N Bukiya
- Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, 71 South Manassas St., Memphis, TN, 38163, USA
| | - Jonathan H Jaggar
- Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, USA
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