δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium

Estrada, Juan A.; Williams, Arthur G.; Sun, Jie; Gonzalez, Leticia; Downey, H. Fred; Caffrey, James L.; Mallet, Robert T.

doi:10.1007/s00395-016-0538-5

Cited by 26 publications

(43 citation statements)

References 70 publications

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“…DOR signaling acts at multiple levels, including the inhibition of hypoxic/ischemic disruption of ionic homeostasis [20,29,47], and the regulation of survival/death signals [48,49]. Estrada et al found that DOR protected canine myocardium from cardiac injury under intermittent hypoxia, which demonstrated the important roles of DOR in cardioprotection against hypoxia [50]. In this study, several miRNAs were identified that respond to DOR activation under normoxic and/or hypoxic conditions and most of them were increased in response to DOR activation at various time points, suggesting that DOR signaling regulates cardiac miRNAs.…”

Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Zhi

Li²,

Shao³

et al. 2016

Cell Physiol Biochem

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Background: Hypoxic/ischemic injury to the heart is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs (miRNAs) are involved in hypoxic/ischemic events, and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering miRNA expression in the heart under hypoxic conditions. The present study aimed to test our hypothesis. Methods: Male Sprague Dawley rats were exposed to hypoxia (9.5-10% O₂) for 1, 5, or 10 days with or without DOR activation. The target miRNAs were selected from TaqMan low-density array (TLDA) data and were further analyzed by quantitative real-time PCR. Results: We found that: 1) hypoxia alters the miRNA expression profiles depending on the hypoxic duration; 2) DOR activation shifts miRNA expression profiles in normoxic conditions and upregulates miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, and miR-338; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression and increases the levels of miR-128a-3p, miR-134-5p, miR-135a, miR-193a-3p, miR-196a, miR-324-3p, miR-141, miR-200b, and miR-324-3p. For example, miR-196c-5p decreased by 50% while miR-135a-5p increased 2.9 fold after 10 days under hypoxic conditions. Moreover, DOR activation further strengthened the hypoxia-induced increase of the levels of miR-7a-5p. When DOR was activated using UFP-512, the level of miR-107-3p significantly increased 1 day after the administration of UFP-512, but gradually decreased back to normal under normoxia. Conclusion: Hypoxia significantly modifies the miRNA profile in the heart, which can be mimicked or modified by DOR activation. Defining the targeted pathways that regulate the diverse cellular and molecular functions of miRNAs may provide new insights into potential therapies for hypoxic/ischemic injury of the heart.

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Section: Discussionmentioning

confidence: 99%

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Zhi

Li²,

Shao³

et al. 2016

Cell Physiol Biochem

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“…[171][172][173] Interestingly, administration of antioxidant NAC prior to each IHT session abolished protective effects of IHT on ischemic myocardium in dogs. 174 The pineal hormone melatonin is an antioxidant and a free radical scavenger that is deficient in many AD patients. Melatonin also possesses antiamyloidogenic properties.…”

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confidence: 99%

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

Манухина

Downey

Shi

et al. 2016

Exp Biol Med (Maywood)

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Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso-and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic epilepsy, spinal cord injury, and alcohol withdrawal stress have also been reported. Further research on the potential benefits of IHT in AD and other brain pathologies is warranted.

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“…As DOR roles in this setting are not completely understood; DOR blockade effects were evaluated through monitoring its interference with 20-days of hypoxic exposure protection on dogs before occluding coronary arteries. Naltrindole administration at every exposure session almost completely abolished the beneficial effects of hypoxia pre-conditioning through monitoring the severity of arrhythmias and infarct sizes, which indicates the key roles of endogenous DOR activity in cardiac protective conditioning (21) . In addition to the established DOR protective roles, mu receptors have also been investigated; sedatin, which is a synthetic mixed agonist of delta/mu receptors, was investigated on isolated pulmonary fibroblastic cells, sedatin significantly reduced oxidative stress effects on cellular morphology and DNA synthesis ability (22) .…”

Section: Dor Cardioprotective Effectsmentioning

confidence: 78%

Promising Therapeutic Agents: Delta Opioid Receptor Agonists

Bazzari

2017

IAM

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Adequate characterization of the endogenous opioid system's peptides and receptors; in addition to, the development of highly selective ligands, have improved research approaches and understanding the roles of this system. DeltaOpioid Receptor (DOR) was found to exhibit distinctive pharmacological profile and tissue distribution compared to other opioid receptors. Hence, DOR has been extensively investigated in the last decade as a potential target in the treatment of various disorders. Research findings indicate high potential of DOR agonists in the modulation of brain as well as cardiovascular system functions. DOR activation was found to display cytoprotective effects against ischemia/reperfusion injury in neurons and cardiomyocytes. DOR affects cellular functions on the level of gene expression, ion channels, enzymatic activity and membrane-receptors functions through multiple signaling pathways and second messenger systems. Moreover, DOR has been implicated in mood disorders; in vivo administration of DOR agonists and enkephalinase inhibitors had significant anxiolytic and antidepressant effects. More recent research findings have shown consistent and statistically significant results on DOR activation beneficial effects in cardiac conditioning, neural ischemia protection, anxiety and depression management. Further advances in research would potentially reveal the exact molecular mechanisms underlying DOR functions in relation to receptor subtypes and signaling pathways.

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δ-Opioid receptor (DOR) signaling and reactive oxygen species (ROS) mediate intermittent hypoxia induced protection of canine myocardium

Cited by 26 publications

References 70 publications

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

δ-Opioid Receptor Activation and MicroRNA Expression in the Rat Heart Under Prolonged Hypoxia

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

Promising Therapeutic Agents: Delta Opioid Receptor Agonists

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