Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge

Alekseev, Alexey E.; Park, Sungjo; Pimenov, O. Yu.; Reyes, Santiago; Terzic, André

doi:10.1016/j.pharmthera.2019.01.007

Cited by 17 publications

(5 citation statements)

References 156 publications

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“…α2-adrenergic receptors (α2-ARs) mediate various physiological functions, such as regulation of blood perfusion and oxygen supply (Geevarghese et al, 2023). There are three subtypes of α2-ARs distributed in the body, namely, α2A, α2B, and α2C, which are principally associated with presynaptic neurons and regulate the activity and neuronal release of norepinephrine (Alekseev et al, 2019;Lähdesmäki et al, 2004). α2A and α2C receptors are widely distributed in the brain and mediate some classical functions, including sedation, analgesia, hypnosis, stress response and so on (Kable et al, 2000;Sallinen et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

He,

Yin,

Wang

et al. 2024

Metab Brain Dis

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Section: Discussionmentioning

confidence: 99%

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

He,

Yin,

Wang

et al. 2024

Metab Brain Dis

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“…α2-AR is an inhibitory G protein-coupled receptor that mainly acts via G inhibitory (Gi) protein. 28 Gi protein is a heterotrimeric G protein 29 that can induce STAT3 phosphorylation. 30 It is rational to speculate that DEX promotes the STAT3 phosphorylation via α2-AR and downstream Gi proteins.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

Zhaorong

Hong

Wen

et al. 2023

Anesthesia &Amp; Analgesia

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BACKGROUND: Myocardial infarction is a common perioperative complication, and blood flow restoration causes ischemia/reperfusion injury (IRI). Dexmedetomidine (DEX) pretreatment can protect against cardiac IRI, but the mechanism is still insufficiently understood. METHODS: In vivo, myocardial ischemia/reperfusion (30 minutes/120 minutes) was induced via ligation and then reperfusion of the left anterior descending coronary artery (LAD) in mice. Intravenous infusion of 10 μg/kg DEX was performed 20 minutes before ligation. Moreover, the α2-adrenoreceptor antagonist Yohimbine and STAT3 inhibitor Stattic were applied 30 minutes ahead of DEX infusion. In vitro, hypoxia/reoxygenation (H/R) with DEX pretreatment for 1 hour was performed in isolated neonatal rat cardiomyocytes. In addition, Stattic was applied before DEX pretreatment. RESULTS: In the mouse cardiac ischemia/reperfusion model, DEX pretreatment lowered the serum creatine kinase-MB isoenzyme (CK-MB) levels (2.47 ± 0.165 vs 1.55 ± 0.183; P < .0001), downregulated the inflammatory response (P ≤ .0303), decreased 4-hydroxynonenal (4-HNE) production and cell apoptosis (P = .0074), and promoted the phosphorylation of STAT3 (4.94 ± 0.690 vs 6.68 ± 0.710, P = .0001), which could be blunted by Yohimbine and Stattic. The bioinformatic analysis of differentially expressed mRNAs further confirmed that STAT3 signaling might be involved in the cardioprotection of DEX. Upon H/R treatment in isolated neonatal rat cardiomyocytes, 5 μM DEX pretreatment improved cell viability (P = .0005), inhibited reactive oxygen species (ROS) production and calcium overload (both P ≤ .0040), decreased cell apoptosis (P = .0470), and promoted STAT3 phosphorylation at Tyr705 (0.102 ± 0.0224 vs 0.297 ± 0.0937; P < .0001) and Ser727 (0.586 ± 0.177 vs 0.886 ± 0.0546; P = .0157), which could be abolished by Stattic. CONCLUSIONS: DEX pretreatment protects against myocardial IRI, presumably by promoting STAT3 phosphorylation via the α2-adrenoreceptor in vivo and in vitro.

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“…However, studies of two human α2B receptor variants suggested that they might protect cardiac muscle against sympathetic/catecholaminergic overstimulation ( 45 , 46 ). Furthermore, recent preclinical studies underlined the potential of these receptors to safeguard cardiac muscle under adrenergic surge by governing intracellular Ca2 + handling and contractility ( 47 , 48 ), and therefore reduce the risk of HF. α2B receptor stimulation induces also platelet aggregation ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

Baudier,

Fougerousse,

Asselbergs

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF.MethodsGenetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases).ResultsLower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10−6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12, P = 3 × 10−7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease.ConclusionsThis study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.

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Sarcolemmal α2-adrenoceptors in feedback control of myocardial response to sympathetic challenge

Cited by 17 publications

References 156 publications

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

The alpha2-adrenergic receptor agonist clonidine protects against cerebral ischemia/reperfusion induced neuronal apoptosis in rats

Dexmedetomidine Pretreatment Protects Against Myocardial Ischemia/Reperfusion Injury by Activating STAT3 Signaling

Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

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