Ischemic postconditioning improves the expression of cellular membrane connexin 43 and attenuates the reperfusion injury in rat acute myocardial infarction

He, Hua; Li, Nan; Zhao, Zhihong; Han, Fang; Wang, Xifu; Zeng, Yujie

doi:10.3892/br.2015.485

Cited by 22 publications

(18 citation statements)

References 18 publications

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“…Previous data have indicated that Cx43 does not appear to be important for cardioprotection during ischemic postconditioning [29]. However, recent studies have demonstrated that ischemic postconditioning decreases the rat infarct size by improving the expression of cellular membrane Cx43 [30]. Although increasing evidence suggests that Cx43 is linked to postconditioning [30-33], no studies have addressed the translocation of Cx43 to the mitochondria during postconditioning.…”

Section: Discussionmentioning

confidence: 98%

“…However, recent studies have demonstrated that ischemic postconditioning decreases the rat infarct size by improving the expression of cellular membrane Cx43 [30]. Although increasing evidence suggests that Cx43 is linked to postconditioning [30-33], no studies have addressed the translocation of Cx43 to the mitochondria during postconditioning. The experiments presented herein were designed to determine whether postconditioning altered Cx43 in sarcolemmal and mitochondrial fractions.…”

Section: Discussionmentioning

confidence: 99%

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Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning

Huang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Previous studies have shown that heat shock protein 90 (HSP90)-mediated mitochondrial import of connexin 43 (Cx43) is critical in preconditioning cardioprotection. The present study was designed to test whether postconditioning has the same effect as preconditioning in promoting Cx43 translocation to mitochondria and whether mitochondrial HSP90 modulates this effect. Methods: Cellular models of hypoxic postconditioning (HPC) from rat heart-derived H9c2 cells and neonatal rat cardiomyocytes were employed. The effects of HPC on cardiomyocytes apoptosis were examined by flow cytometry and Hoechst 33342 fluorescent staining. Reactive oxidative species (ROS) production was assessed with the peroxide-sensitive fluorescent probe 2′,7′-dichlorofluorescin in diacetate (DCFH-DA). The anti- and pro-apoptotic markers Bcl-2 and Bax, HSP90 and Cx43 protein levels were studied by Western blot analysis in total cell homogenate and sarcolemmal and mitochondrial fractions. The effects on HPC of the HSP90 inhibitor geldanamycin (GA), ROS scavengers superoxide dismutase (SOD) and catalase (CAT), and small interfering RNA (siRNA) targeting Cx43 and HSP90 were also investigated. Results: HPC significantly reduced hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis. These beneficial effects were accompanied by an increase in Bcl-2 levels and a decrease in Bax levels in both sarcolemmal and mitochondrial fractions. HPC with siRNA targeting Cx43 or the ROS scavengers SOD plus CAT significantly prevented ROS generation and HPC cardioprotection, but HPC with either SOD or CAT did not. These data strongly supported the involvement of Cx43 in HPC cardioprotection, likely via modulation of the ROS balance which plays a central role in HPC protection. Furthermore, HPC increased total and mitochondrial levels of HSP90 and the mitochondria-to-sarcolemma ratio of Cx43; blocking the function of HSP90 with the HSP90 inhibitor geldanamycin (GA) or siRNA targeting HSP90 prevented the protection of HPC and the HPC-induced association of Cx43, indicating that mitochondrial HSP90 was important for mitochondrial translocation of Cx43 during HPC. Conclusion: Mitochondrial HSP90 played a central role in HPC cardioprotection, and its activity was linked to the mitochondrial targeting of Cx43, the activation of which triggered ROS signaling and the subsequent reduction of redox stress. Consequently, its target gene, Bcl-2, was upregulated, and proapoptotic Bax was inhibited in the sarcolemma and mitochondria, ultimately attenuating H/R-induced cardiomyocyte apoptosis. These data reveal a novel mechanism of HPC protection.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning

Huang

et al. 2017

Cell Physiol Biochem

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“…Ischemic conditions can trigger Cx43 hemichannel opening, possibly mediated by the generation of ROS and nitrogen species [ 91 ]. The protection of preconditioning has been confirmed to depend on functional Cx43-formed channels [ 2 ]. Moreover, Cx43 deficiency will lead to ventricular arrhythmia which is the major cause of sudden death in heart failure.…”

Section: The Other Functional Proteins In Mitochondrionmentioning

confidence: 99%

“…As the leading cause of fatality worldwide, ischemic heart diseases (IHD) give rise to widespread loss of cardiomyocytes and subsequent adverse cardiac remodeling [ 1 ]. More than 17 million people had succumbed to IHD in 2008, and the number was estimated to be 23.6 million by 2030 [ 2 ]. Ischemia starves cardiomyocytes of vital oxygen, resulting in severe or irreversible injury to heart [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Mitochondrial Functional Proteins in ROS Production in Ischemic Heart Diseases

Pei

Yang

Zhao

et al. 2016

Oxidative Medicine and Cellular Longevity

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Ischemic heart diseases (IHD) have become the leading cause of death around the world, killing more than 7 million people annually. In IHD, the blockage of coronary vessels will cause irreversible cell injury and even death. As the “powerhouse” and “apoptosis center” in cardiomyocytes, mitochondria play critical roles in IHD. Ischemia insult can reduce myocardial ATP content, resulting in energy stress and overproduction of reactive oxygen species (ROS). Thus, mitochondrial abnormality has been identified as a hallmark of multiple cardiovascular disorders. To date, many studies have suggested that these mitochondrial proteins, such as electron transport chain (ETC) complexes, uncoupling proteins (UCPs), mitochondrial dynamic proteins, translocases of outer membrane (Tom) complex, and mitochondrial permeability transition pore (MPTP), can directly or indirectly influence mitochondria-originated ROS production, consequently determining the degree of mitochondrial dysfunction and myocardial impairment. Here, the focus of this review is to summarize the present understanding of the relationship between some mitochondrial functional proteins and ROS production in IHD.

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“…It has been shown that repeated transitory opening and closing of the coronary artery before continuous reperfusion of the coronary artery (i.e., ischemic postconditioning) offered relief of ischemic-reperfusion damage and delivered notable protection. Some studies [45, 46] have suggested that ischemic postconditioning could affect the expression of substances such as cellular membrane connexin-43 and nitric oxide (NO).…”

Section: Discussionmentioning

confidence: 99%

Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits

Zhang

Liu

et al. 2016

BioMed Research International

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We investigated the cardioprotective effect of renal ischemic postconditioning (RI-PostC) and its mechanisms in a rabbit model. Rabbits underwent 60 min of left anterior descending coronary artery occlusion (LADO) and 6 h of reperfusion. The ischemia-reperfusion (IR) group underwent LADO and reperfusion only. In the RI-PostC group, the left renal artery underwent 3 cycles of occlusion for 30 seconds and release for 30 seconds, before the coronary artery was reperfused. In the RI-PostC + GF109203X group, the rabbits received 0.05 mg/kg GF109203X (protein kinase C inhibitor) intravenously for 10 min followed by RI-PostC. Light microscopy and electron microscopy demonstrated that the RI-PostC group showed less pronounced changes, a smaller infarct region, and less apoptosis than the other two groups. Bcl-2 and Bax protein expression did not differ between the IR and RI-PostC + GF109203X groups. However, in the RI-PostC group, Bcl-2 protein expression was significantly higher and Bax protein expression was significantly lower than in the other two groups (P < 0.05). Changes in heart rate and mean arterial pressure were also smaller in the RI-PostC group than in the other two groups. These results indicate that RI-PostC can ameliorate myocardial ischemia-reperfusion injury and increase the Bcl-2/Bax ratio through a mechanism involving protein kinase C.

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Ischemic postconditioning improves the expression of cellular membrane connexin 43 and attenuates the reperfusion injury in rat acute myocardial infarction

Cited by 22 publications

References 18 publications

Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning

Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning

The Role of Mitochondrial Functional Proteins in ROS Production in Ischemic Heart Diseases

Effects of Renal Ischemic Postconditioning on Myocardial Ultrastructural Organization and Myocardial Expression of Bcl-2/Bax in Rabbits

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