Effects of Pinocembrin Pretreatment on Connexin 43 (Cx43) Protein Expression After Rat Myocardial Ischemia-Reperfusion and Cardiac Arrhythmia

Zhang, Peng; Xu, Jin; Hu, Wei; Dong, Yu; Bai, Xiaolu

doi:10.12659/msm.909162

Cited by 18 publications

(14 citation statements)

References 27 publications

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“…Pinocembrin could also regulate the ion channels (e.g. Na + -K + ATPase, Ca 2+ -Mg 2+ ATPase, and Kir2.1), as well as the gap junction [e.g., Connexin (Cx) 43 Cx43] in myocardial tissues (Zhang et al, 2018). Moreover, our latest study demonstrated that pinocembrin could attenuate autonomic dysfunction and cardiac arrhythmias in myocardial infarction (MI) rats, confirming the cardioprotection of pinocembrin (Ye et al, 2019b).…”

Section: Introductionsupporting

confidence: 59%

Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression

Zhang

et al. 2020

Front. Pharmacol.

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Background: Depression is associated with the increased risk of mortality and morbidity and is an independent risk factor for many cardiovascular diseases. Depression may promote cardiac arrhythmias, but little is known about the mechanisms. Pinocembrin mitigated depressive-like behaviors and exhibited cardioprotective effects in several models; however, whether pinocembrin benefits ventricular arrhythmias in depression models has not been elucidated. Thus, this study was to evaluate the effects of pinocembrin on ventricular fibrillation susceptibility in rat models of depression.Methods: Male Sprague-Dawley rats were randomly assigned into control, control + pinocembrin, MDD (major depressive disorder), and MDP (MDD + pinocembrin) groups, respectively. Depressive-like behaviors, ventricular electrophysiological parameters, electrocardiogram parameters, heart rate variability, ventricular histology, serum norepinephrine, tumor necrosis factor-α, and interleukin-1β were detected. Protein levels in left ventricle were measured by Western blot assays.Results: Compared with the MDD group, pinocembrin significantly mitigated depressive-like behaviors, prolonged ventricular effective refractory period, action potential duration, QT, and corrected QT (QTc) interval, improved heart rate variability, decreased Tpeak–Tend interval, ventricular fibrillation inducibility rate, ventricular fibrosis, ventricular positive nerve densities, and protein expression of tyrosine hydroxylase and growth associated protein-43, reduced serum norepinephrine, tumor necrosis factor-α, interleukin-1β concentrations, and the expression levels of p-IκBα and p-p65, and increased the protein expression of Cx43, Cav1.2, and Kv.4.2 in the MDP group.Conclusion: Pinocembrin attenuates ventricular electrical remodeling, autonomic remodeling, and ion-channel remodeling, lowers ventricular fibrosis, and suppresses depression-induced inflammatory responses, providing new insights in pinocembrin and ventricular arrhythmias in depressed patients.

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Section: Introductionsupporting

confidence: 59%

Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression

Zhang

et al. 2020

Front. Pharmacol.

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“…In the last decade, compelling evidence has indicated a potential role for Cx43 in cardioprotection [49][50][51]. The role of Cx43 in cardiac I/R injury has been extensively investigated in both ex vivo [38,50,[52][53][54] and in vivo models [50,55,56]. The Langendorff perfusion system has proven very useful to explore the impact of ischemic conditions on Cx43 expression, PTMs and cellular localization [52,[57][58][59], while the LAD ligation model of regional I/R injury has been widely used to study the effects of pharmacological interventions involving Cx43 [54][55][56].…”

Section: Cx43 Gap Junction-and Hemi-channels and Cardiac I/r Injurymentioning

confidence: 99%

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

et al. 2020

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Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo animal models of cardiac ischemia/reperfusion (I/R) injury are robustly used in research. Connexin43 (Cx43), the predominant gap junction channel-forming protein in cardiomyocytes, has emerged as a cardioprotective target. Cx43 posttranslational modifications as well as cellular distribution are altered during cardiac reperfusion injury, inducing phosphorylation states and localization detrimental to maintaining intercellular communication and cardiac conduction. Pre- (before ischemia) and post- (after ischemia but before reperfusion) conditioning can abrogate this injury process, preserving Cx43 and reducing cell death. Pre-/post-conditioning has been shown to largely rely on the presence of Cx43, including mitochondrial Cx43, which is implicated to play a major role in pre-conditioning. Posttranslational modifications of Cx43 after injury alter the protein interactome, inducing negative protein cascades and altering protein trafficking, which then causes further damage post-I/R injury. Recently, several peptides based on the Cx43 sequence have been found to successfully diminish cardiac injury in pre-clinical studies.

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“…Pinocembrin induces ER stress via the inositol-requiring endonuclease 1 α/X-box binding protein 1 pathway and then triggers caspase-12/-4 mediated apoptosis by suppressing autophagy through the activation of PI3K/Akt/mTOR pathway [9]. Pinocembrin also reduced ventricular arrhythmias in I/R rats by enhancing Na + -K + ATPase and Ca 2+ -Mg 2+ ATPase activity and up-regulating Cx43 and Kir2.1 protein expression [61].…”

Section: Pharmacological Effects Of Pinocembrinmentioning

confidence: 99%

Advances in Biosynthesis, Pharmacology, and Pharmacokinetics of Pinocembrin, a Promising Natural Small-Molecule Drug

et al. 2019

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Pinocembrin is one of the most abundant flavonoids in propolis, and it may also be widely found in a variety of plants. In addition to natural extraction, pinocembrin can be obtained by biosynthesis. Biosynthesis efficiency can be improved by a metabolic engineering strategy and a two-phase pH fermentation strategy. Pinocembrin poses an interest for its remarkable pharmacological activities, such as neuroprotection, anti-oxidation, and anti-inflammation. Studies have shown that pinocembrin works excellently in treating ischemic stroke. Pinocembrin can reduce nerve damage in the ischemic area and reduce mitochondrial dysfunction and the degree of oxidative stress. Given its significant efficacy in cerebral ischemia, pinocembrin has been approved by China Food and Drug Administration (CFDA) as a new treatment drug for ischemic stroke and is currently in progress in phase II clinical trials. Research has shown that pinocembrin can be absorbed rapidly in the body and easily cross the blood–brain barrier. In addition, the absorption/elimination process of pinocembrin occurs rapidly and shows no serious accumulation in the body. Pinocembrin has also been found to play a role in Parkinson’s disease, Alzheimer’s disease, and specific solid tumors, but its mechanisms of action require in-depth studies. In this review, we summarized the latest 10 years of studies on the biosynthesis, pharmacological activities, and pharmacokinetics of pinocembrin, focusing on its effects on certain diseases, aiming to explore its targets, explaining possible mechanisms of action, and finding potential therapeutic applications.

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Effects of Pinocembrin Pretreatment on Connexin 43 (Cx43) Protein Expression After Rat Myocardial Ischemia-Reperfusion and Cardiac Arrhythmia

Cited by 18 publications

References 27 publications

Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression

Pinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

Advances in Biosynthesis, Pharmacology, and Pharmacokinetics of Pinocembrin, a Promising Natural Small-Molecule Drug

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