Lipids in gap junction assembly and function

Malewicz, Barbara; Kumar, V. V.; Johnson, Ross G.; Baumann, Wolfgang J.

doi:10.1007/bf02538083

Cited by 60 publications

(38 citation statements)

References 99 publications

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“…The cholesterol enrichment of cell membranes after dietary hypercholesterolemia may alter the assembly and distribution of Cx43. 41 Meyer et al 42 have treated cells with cholesterol in serum-free media and observed a decrease in gap junction assembly. The dietary hypercholesterolemia, increasing nonspecific effectors of inflammation 43 and the oxidative stressdependent processes of macrophages within the myocardium, 44 was shown to activate JNK in this study.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Previous in vitro studies have shown that the lipid content of the plasma membrane, as well as the extracellular space, have diverse effects on gap junctions. 22 In animal studies investigating the effect of hyperlipidemia on endothelial gap junctions, a recent ultrastructural study reported that fewer aortic endothelial gap junctions were present in rats fed a long-term, cholesterolenriched diet compared with those fed normal chow. 6 However, because immunohistochemical examination was not conducted in that study, the details of the component connexins remained unknown.…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Endothelial Connexin37 and Connexin40 in Hyperlipidemic Mice

Yeh

Lu²,

Wu³

et al. 2003

ATVB

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Objective-We sought to clarify the response of endothelial connexins to hyperlipidemia and lipid-lowering therapy. Methods and Results-Aortic endothelial gap junctions were analyzed by en face immunoconfocal microscopy and electron microscopy in C57BL/6 mice subjected to the following regimens: (1) normal chow (NC) for 3 months (3 mo), (2) NC for 9 mo, (3) NC for 3 mo, followed by a cholesterol-enriched diet (CED) for 6 mo, (4) NC for 3 mo and CED for 6 mo, with simvastatin in the final week, and (5) (in apoprotein E [apoE]-deficient mice) NC and examined at 3 mo and 7 to 9 mo. In wild-type mice, connexin37 (Cx37) and Cx40 were markedly downregulated in the CED-fed animals compared with those fed NC (CED vs 9-mo NC, 77% reduction in Cx37 and 65% reduction in Cx40; both PϽ0.01).After simvastatin treatment, Cx40 remained depressed, but Cx37 recovered to 94% of the level found in non-cholesterol-fed animals (PϽ0.01). Electron microscopy demonstrated that gap junctions were smaller in animals fed the CED compared with those given simvastatin and with controls fed NC (PϽ0.01). Endothelial connexins were rare in the atherosclerotic plaques of apoE-deficient mice. 3,4 Studies in animal models have demonstrated that hyperlipidemia is associated with alterations to the junctions between neighboring endothelial cells, including gap junctions. 5,6 Gap junctions are cellmembrane protein channels made of connexin molecules, which belong to a multigene family. In mammals, connexin37 (Cx37), Cx40, and Cx43 are known to be variously expressed in endothelial cells of different sites within the vascular tree. 7,8 In vitro studies indicate that the properties of gap-junctional channels are determined by their connexin makeup, 9 and gene-knockout studies show that mice deficient in specific type(s) of endothelial connexins are associated with vascular functional defects or morphological changes. 10 -12 Furthermore, distinct differences in the distribution and expression between connexin types in the vascular wall have been demonstrated in processes related to atherogenesis, such as hypertension, 13,14 postinjury regeneration, 15,16 and aging, 17 raising the possibility that each connexin type might play a distinctive role. Although recent investigations of hyperlipidemia induced by different experimental approaches in animal models of different species have reported that endothelial gap junctions and connexins change in the hyperlipidemic state, 5,6 whether the change is specific to the model remained unclear. In addition, in those studies, the extent of endothelium examined was limited, and knowledge regarding the response of each endothelial connexin to lipid-lowering therapy was lacking. Conclusions-MouseIn this study, we examined the expression patterns of endothelial gap junctions and connexins in C57BL/6 mice fed a cholesterol-enriched diet (CED) and in the same strain of mice deprived of the apoprotein E (apoE) gene. In addition, the effect of statins, a class of potent, lipidlowering agents reported to decrease progressio...

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“…Specific lipids, such as cholesterol and low-density lipoprotein, also appear to be required for and modulate the efficiency of channel assembly. Both inhibitory as well as stimulatory effects have been reported, depending upon the concentrations used (Malewicz et al, 1990;Meyer et al, 1990). Finally, alkaline extracellular pH promotes junctional communication between oocyte pairs , presumably by interacting with intrinsic determinants (cysteine residues on the extracellular loops of connexins, see below).…”

Section: Docking and Gatingmentioning

confidence: 99%

Connections with Connexins: the Molecular Basis of Direct Intercellular Signaling

Bruzzone

White²,

Paul

1996

European Journal of Biochemistry

1,201

422

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Adjacent cells share ions, second messengers and small metabolites through intercellular channels which are present in gap junctions. This type of intercellular communication permits coordinated cellular activity, a critical feature for organ homeostasis during development and adult life of multicellular organisms. Intercellular channels are structurally more complex than other ion channels, because a complete cell-to-cell channel spans two plasma membranes and results from the association of two half channels, or connexons, contributed separately by each of the two participating cells, Each connexon, in turn, is a multimeric assembly of protein subunits. The structural proteins comprising these channels, collectively called connexins, are members of a highly related multigene family consisting of at least 13 members.Since the cloning of the first connexin in 1986, considerable progress has been made in our understanding of the complex molecular switches that control the formation and permeability of intercellular channels. Analysis of the mechanisms of channel assembly has revealed the selectivity of inter-connexin interactions and uncovered novel characteristics of the channel permeability and gating behavior. Structure/ function studies have begun to provide a molecular understanding of the significance of connexin diversity and demonstrated the unique regulation of connexins by tyrosine kinases and oncogenes. Finally, mutations in two connexin genes have been linked to human diseases. The development of more specific approaches (dominant negative mutants, knockouts, transgenes) to study the functional role of connexins in organ homeostasis is providing a new perception about the significance of connexin diversity and the regulation of intercellular communication.

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Lipids in gap junction assembly and function

Cited by 60 publications

References 99 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

Reduced Expression of Endothelial Connexin37 and Connexin40 in Hyperlipidemic Mice

Connections with Connexins: the Molecular Basis of Direct Intercellular Signaling

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