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Vascular dysfunctions such as vascular hyporeactivity following ischemic/hypoxic injury are a major cause of death in injured patients. In this study, we showed that treatment with mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor of dynamin-related protein 1 (Drp1), significantly improved vascular reactivity in ischemic rats by attenuating oxidative stress. The antioxidative effects of Mdivi-1 were relatively Drp1-independent, and possibly due to an increase in the levels of the antioxidant enzymes, SOD1 and catalase, as well as to enhanced Nrf2 expression. In addition, we found that while Mdivi-1 had little effect on Drp1 GTPase activity in vascular smooth muscle cells, it inhibited hypoxia-induced Drp1 phosphorylation at Ser-616, reducing excessive mitochondrial fission and slightly enhancing mitochondrial fusion. These effects possibly contributed to vascular protection at an early stage of ischemic/hypoxic injury. Finally, Mdivi-1 stabilized hemodynamics, increased vital organ perfusion, and improved rat survival after ischemic/hypoxic injury, proving a promising therapeutic agent for ischemic/hypoxic injury.

Mitochondrial dynamics play a critical role in mitochondrial function and signaling. Although mitochondria play a critical role in hypoxia/ischemia, the further mechanisms between mitochondrial dynamics and ischemia are still unclear. The current study aimed to determine the role of mitofusin 2, a key regulator of mitochondrial fusion, in a hypoxic model and to explore a novel strategy for cerebral ischemia via modulation of mitochondrial dynamics. To the best of our knowledge, this is the first study to investigate both mitochondrial function and molecular pathways to determine the role of mitofusin 2 in hypoxia-induced neuronal apoptosis. In vivo , C57BL/6 mice (male, 19–25 g) underwent a permanent middle cerebral artery occlusion for 12 or 24 h ( n = 6 per group). In vitro , cobalt chloride was used to mimic hypoxia in immortalized hippocampal neurons. Down- or up-regulation of Mfn2 was induced to investigate the role of Mfn2 in hypoxia, especially in mitochondrial function and signaling pathways. The findings demonstrated that decreased mitofusin 2 occurred both in vivo and in vitro hypoxic models; second, the anti-apoptotic effect of Mfn2 may work via restoration of mitochondrial function; third, the modulation of the B Cell Leukemia 2/Bcl-2 Associated X protein and extracellular signal-regulated kinase 1/2 signaling pathways highlight the role of Mfn2 in signaling pathways beyond fusion. In summary, depletion of mitofusin 2 would lead to apoptosis both in normal or hypoxic conditions; however, mitofusin 2 overexpression could attenuate hypoxia-induced apoptosis, which represents a potential novel strategy for neuroprotection against ischemic brain damage. [ABSTRACT FROM AUTHOR]

To evaluate the protective properties of peptides related functionally and/or structurally to vasoactive intestinal peptide (VIP), PC12 cultures were treated with iodoacetate as a model for neuronal ischemic/hypoxic injury. Brain tissue can be pre-conditioned against lethal ischemia by several mechanisms including sub-lethal ischemia, moderate hypoglycemia, heat shock, and growth factors. In the present study, a superactive VIP lipophilic analog (Stearyl-Norleucine17-VIP; SNV) was used to pre-condition media of PC12 cells. After removal of the conditioned media, the cultures were exposed to iodoaceate, which inhibits glycolysis. Protective efficacy against iodoacetate-induced injury was assessed by the measurements of lactate dehydrogenase (LDH) activity in the media. Treatment with iodoacetate for 2.5 h produced a twofold increase in LDH activity in the media. The protective effect of SNV had an EC50 of 1 pM. Comparison of the preconditioning time required for full protection by SNV showed no apparent difference between a 15 min and a 2 h incubation period prior to the addition of iodoacetate. Iodoacetate treatment produced a 20% decrease in the RNA transcripts encoding activity-dependent neuroprotective protein (ADNP), a novel glia-derived protein that is regulated by VIP. The iodoacetate-associated reduction in ADNP mRNA was prevented by pre-treatment with SNV. These effects imply that SNV provides a regulatory mechanism for ADNP synthesis during glycolytic stress. Furthermore, a short exposure to SNV provided potent protection from iodoacetate-induced toxicity suggesting that SNV may have therapeutic value in the treatment of ischemic/hypoxic injury. [ABSTRACT FROM AUTHOR]

Vascular dysfunctions such as vascular hyporeactivity following ischemic/hypoxic injury are a major cause of death in injured patients. In this study, we showed that treatment with mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor of dynamin-related protein 1 (Drp1), significantly improved vascular reactivity in ischemic rats by attenuating oxidative stress. The antioxidative effects of Mdivi-1 were relatively Drp1-independent, and possibly due to an increase in the levels of the antioxidant enzymes, SOD1 and catalase, as well as to enhanced Nrf2 expression. In addition, we found that while Mdivi-1 had little effect on Drp1 GTPase activity in vascular smooth muscle cells, it inhibited hypoxia-induced Drp1 phosphorylation at Ser-616, reducing excessive mitochondrial fission and slightly enhancing mitochondrial fusion. These effects possibly contributed to vascular protection at an early stage of ischemic/hypoxic injury. Finally, Mdivi-1 stabilized hemodynamics, increased vital organ perfusion, and improved rat survival after ischemic/hypoxic injury, proving a promising therapeutic agent for ischemic/hypoxic injury., (Copyright © 2020 Army Medical University. Published by Elsevier B.V. All rights reserved.)

Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ . Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO 2 ), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O 2 ) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO 2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)