Cargando…
The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission
BACKGROUND: The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in nonhomeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732383/ https://www.ncbi.nlm.nih.gov/pubmed/33343806 http://dx.doi.org/10.1155/2020/4132785 |
_version_ | 1783622081555988480 |
---|---|
author | Lei, Yan Peng, Xiaoyong Hu, Yi Xue, Mingying Li, Tao Liu, Liangming Yang, Guangming |
author_facet | Lei, Yan Peng, Xiaoyong Hu, Yi Xue, Mingying Li, Tao Liu, Liangming Yang, Guangming |
author_sort | Lei, Yan |
collection | PubMed |
description | BACKGROUND: The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in nonhomeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function and investigated the mechanisms. METHODS: Rats that had been subjected to THS and hypoxia-treated vascular smooth muscle cells (VSMCs) were used in this study. The effects of Cal on cardiovascular function, animal survival, hemodynamics, and vital organ function in THS rats and the relationship to oxidative stress, mitochondrial fusion-fission, and microRNA (miR-208a) were investigated. RESULTS: Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS in vivo and in vitro. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation (the key element for VSMC contraction). Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal suppressed oxidative stress in THS rats and hypoxic-VSMCs. Meanwhile, THS induced expression of mitochondrial fission proteins Drp1 and Fis1 and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1. In hypoxic-VSMCs, Cal inhibited mitochondrial fragmentation and preserved mitochondrial morphology. In addition, miR-208a mimic decreased Fis1 expression, and miR-208a inhibitor prevented Cal-induced Fis1 downregulation in hypoxic-VSMCs. CONCLUSION: Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, and the beneficial effects result from its protection of vascular function via inhibition of oxidative stress and miR-208a-mediated mitochondrial fission. |
format | Online Article Text |
id | pubmed-7732383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-77323832020-12-18 The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission Lei, Yan Peng, Xiaoyong Hu, Yi Xue, Mingying Li, Tao Liu, Liangming Yang, Guangming Oxid Med Cell Longev Research Article BACKGROUND: The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in nonhomeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function and investigated the mechanisms. METHODS: Rats that had been subjected to THS and hypoxia-treated vascular smooth muscle cells (VSMCs) were used in this study. The effects of Cal on cardiovascular function, animal survival, hemodynamics, and vital organ function in THS rats and the relationship to oxidative stress, mitochondrial fusion-fission, and microRNA (miR-208a) were investigated. RESULTS: Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS in vivo and in vitro. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation (the key element for VSMC contraction). Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal suppressed oxidative stress in THS rats and hypoxic-VSMCs. Meanwhile, THS induced expression of mitochondrial fission proteins Drp1 and Fis1 and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1. In hypoxic-VSMCs, Cal inhibited mitochondrial fragmentation and preserved mitochondrial morphology. In addition, miR-208a mimic decreased Fis1 expression, and miR-208a inhibitor prevented Cal-induced Fis1 downregulation in hypoxic-VSMCs. CONCLUSION: Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, and the beneficial effects result from its protection of vascular function via inhibition of oxidative stress and miR-208a-mediated mitochondrial fission. Hindawi 2020-12-03 /pmc/articles/PMC7732383/ /pubmed/33343806 http://dx.doi.org/10.1155/2020/4132785 Text en Copyright © 2020 Yan Lei et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Lei, Yan Peng, Xiaoyong Hu, Yi Xue, Mingying Li, Tao Liu, Liangming Yang, Guangming The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title | The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title_full | The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title_fullStr | The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title_full_unstemmed | The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title_short | The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission |
title_sort | calcilytic drug calhex-231 ameliorates vascular hyporesponsiveness in traumatic hemorrhagic shock by inhibiting oxidative stress and mir-208a-mediated mitochondrial fission |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732383/ https://www.ncbi.nlm.nih.gov/pubmed/33343806 http://dx.doi.org/10.1155/2020/4132785 |
work_keys_str_mv | AT leiyan thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT pengxiaoyong thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT huyi thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT xuemingying thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT litao thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT liuliangming thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT yangguangming thecalcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT leiyan calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT pengxiaoyong calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT huyi calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT xuemingying calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT litao calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT liuliangming calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission AT yangguangming calcilyticdrugcalhex231amelioratesvascularhyporesponsivenessintraumatichemorrhagicshockbyinhibitingoxidativestressandmir208amediatedmitochondrialfission |