Gap Junction Uncoupler Heptanol Prevents Cell-to-Cell Progression of Hypercontracture and Limits Necrosis During Myocardial Reperfusion

Garcı́a-Dorado, David; Inserte, Javier; Ruiz‐Meana, Marisol; González, Miguel A.; Solares, Julia; Julià, Margarita Oliveras; Barrabés, José A.; Soler‐Soler, Jordi

doi:10.1161/01.cir.96.10.3579

Cited by 181 publications

(142 citation statements)

References 25 publications

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“…31 All of these data support our view that in the hyperlipidemic rabbits downregulation of cardiomyocyte gap junctions may contribute to the impaired systolic function.…”

Section: Discussionsupporting

confidence: 75%

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Lin

Yeh

et al. 2005

Laboratory Investigation

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The effects of hypercholesterolemia on the myocardium per se include electrophysiological and mechanical alterations. Since gap junctions are essential in electromechanical coupling throughout the heart, we examined the correlation between the temporal expression of cardiac connexin 43 (Cx43), contractile function, and conduction velocity in cholesterol-fed rabbits. After a 12-week feeding period, serum cholesterol levels gradually increased (Po0.001). In contrast, expression of cardiomyocyte Cx43 protein progressively decreased (60% reduction at 12 weeks, Po0.001). Such a reduction was also demonstrated by immunoconfocal microscopy, which further showed redistribution of Cx43 gap junctions at the lateral cell membrane. The downregulation of Cx43 protein was associated with increased levels of Cx43 mRNA (3.5 -fold at 12 weeks, Po0.001) and phosphorylated c-Jun N-terminal kinase (three-fold at 12 weeks, P ¼ 0.001). Functionally, although fractional shortening of the left ventricle remained unchanged throughout the feeding protocol, the cholesterol-fed rabbits had a reduced cardiac cycle-dependent variation of integrated backscatters, a decreased mitral ring systolic velocity, and an increased modified Tei index (all Po0.001), all of which indicated impaired intrinsic myocardial contractility and attenuated ventricular systolic performance. In Langendorff-perfused hearts of cholesterol-fed rabbits, decreased conduction velocity was observed (Po0.005). Withdrawal of the cholesterol-enriched diet for 18 weeks restored the contractile parameters and Cx43 protein expression. These findings suggest that Cx43 is highly involved in the molecular mechanism of hypercholesterolemia-induced cardiac contractile dysfunction and dysrhythmias.

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“…31 All of these data support our view that in the hyperlipidemic rabbits downregulation of cardiomyocyte gap junctions may contribute to the impaired systolic function.…”

Section: Discussionsupporting

confidence: 75%

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Lin

Yeh

et al. 2005

Laboratory Investigation

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“…Additionally, hypercontracture has been shown to be transmitted from cell to cell through GJs in paired cardiomyocytes. 6,7 These observations suggest that CBN is propagated from cell to cell through GJs, but not through hemichannels during reperfusion. CBN is distributed exclusively to the lateral borders of risk area in the mid-myocardium and does not propagate in the non-risk area beyond the border (Figure 7).…”

Section: Involvement Of Gjic In Spread Of Cbn and Infarct Developmentmentioning

confidence: 90%

Ischemia Enhances Translocation of Connexin43 and Gap Junction Intercellular Communication, Thereby Propagating Contraction Band Necrosis After Reperfusion

Shintani-Ishida

Unuma

Yoshida

2009

Circ J

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“…GJs coordinate metabolic and electrical signals at long distances from the original stimulus site (Saez et al, 2003). In pathological conditions, inhibition of astrocyte GJs has been shown either to reduce (Garcia-Dorado et al, 1997;Rawanduzy et al, 1997;Cotrina et al, 1998) or to enhance (Blanc et al, 1998;Siushansian et al, 2001;Frantseva et al, 2002) damage. The mechanisms by which GJs mediate these effects could be by reducing the ability of the astrocytes to remove extracellular toxic soluble factors and/or by maintaining the propagation of proapoptotic or survival signals between dying and healthy cells.…”

Section: Introductionmentioning

confidence: 99%

Gap Junctions Mediate Human Immunodeficiency Virus-Bystander Killing in Astrocytes

Eugenín¹,

Berman²

2007

J. Neurosci.

115

172

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Human immunodeficiency virus (HIV) entry into the CNS is an early event after infection, resulting in neurological dysfunction in a significant number of individuals. As people with acquired immunodeficiency syndrome (AIDS) live longer, the prevalence of cognitive impairment is increasing, despite antiretroviral therapy. The mechanisms that mediate CNS dysfunction are still not completely understood, and include inflammation, viral presence, and/or replication. In this report, we characterize a novel role of gap junctions in transmitting and thereby amplifying toxic signals originating from HIV-infected astrocytes that trigger cell death in uninfected astrocytes. HIV-infected astrocytes were resistant to apoptosis; however, uninfected astrocytes forming gap junctions with infected astrocytes were apoptotic. Gap junction blockers abolished apoptosis in uninfected astrocytes, supporting the role of these channels in amplifying cell death. Our findings describe a novel mechanism of toxicity within the brain, triggered by low numbers of HIV-infected astrocytes and amplified by gap junctions, contributing to the pathogenesis of NeuroAIDS.

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Gap Junction Uncoupler Heptanol Prevents Cell-to-Cell Progression of Hypercontracture and Limits Necrosis During Myocardial Reperfusion

Cited by 181 publications

References 25 publications

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

Ischemia Enhances Translocation of Connexin43 and Gap Junction Intercellular Communication, Thereby Propagating Contraction Band Necrosis After Reperfusion

Gap Junctions Mediate Human Immunodeficiency Virus-Bystander Killing in Astrocytes

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