Abstract
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.
Highlights
Trauma is the leading cause of death for people under 44 years of age, and about 40% of trauma-related mortality is attributed to hemorrhage and its sequelae [1, 2]
Our results demonstrate that Calhex-231 (Cal), a specific inhibitor of calcium-sensing receptor (CaSR), has a mitigating effect on traumatic hemorrhagic shock by improving vascular hyporesponsiveness and reducing mitochondrial dysfunction
The vascular function protection conferred by Cal may be attributed to attenuation of oxidative stress and reversal of damage to mitochondrial morphology and function, and miR-208a is involved in Cal-regulating mitochondrial fission. These findings show the important role played by CaSR in the regulation of vascular reactivity after traumatic hemorrhagic shock (THS), and the potential offered by its allosteric modulator Calhex-231 for the treatment of critical illness
Summary
Trauma is the leading cause of death for people under 44 years of age, and about 40% of trauma-related mortality is attributed to hemorrhage and its sequelae [1, 2]. Despite the development of new technologies and therapeutic methods in recent years, the management of trauma/hemorrhage (T/H) patients remains a challenge Cardiovascular dysfunction, such as vascular hyporesponsiveness, is a welldocumented phenomenon and a major cause of death in T/H patients [3,4,5]. 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. Cal suppressed oxidative stress in THS rats and hypoxic-VSMCs. THS induced expression of mitochondrial fission proteins Drp and Fis and decreased expression of mitochondrial fusion protein Mfn in vascular tissues. 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
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