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A central role of connexin 43 in hypoxic preconditioning.

ABSTRACT: Preconditioning is an endogenous mechanism in which a nonlethal exposure increases cellular resistance to subsequent additional severe injury. Here we show that connexin 43 (Cx43) plays a key role in protection afforded by preconditioning. Cx43 null mice were insensitive to hypoxic preconditioning, whereas wild-type littermate mice exhibited a significant reduction in infarct volume after occlusion of the middle cerebral artery. In cultures, Cx43-deficient cells responded to preconditioning only after exogenous expression of Cx43, and protection was attenuated by small interference RNA or by channel blockers. Our observations indicate that preconditioning reduced degradation of Cx43, resulting in a marked increase in the number of plasma membrane Cx43 hemichannels. Consequently, efflux of ATP through hemichannels led to accumulation of its catabolic product adenosine, a potent neuroprotective agent. Thus, adaptive modulation of Cx43 can offset environmental stress by adenosine-mediated elevation of cellular resistance.

SUBMITTER: Lin JH

PROVIDER: S-EPMC6670356 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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A central role of connexin 43 in hypoxic preconditioning.

Lin Jane H-C JH Lou Nanhong N Kang Ning N Takano Takahiro T Hu Furong F Han Xiaoning X Xu Qiwu Q Lovatt Ditte D Torres Arnulfo A Willecke Klaus K Yang Jay J Kang Jian J Nedergaard Maiken M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080101 3

Preconditioning is an endogenous mechanism in which a nonlethal exposure increases cellular resistance to subsequent additional severe injury. Here we show that connexin 43 (Cx43) plays a key role in protection afforded by preconditioning. Cx43 null mice were insensitive to hypoxic preconditioning, whereas wild-type littermate mice exhibited a significant reduction in infarct volume after occlusion of the middle cerebral artery. In cultures, Cx43-deficient cells responded to preconditioning only ...[more]

PMID: 18199768

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Project description:We report that elevated connexin-43 (Cx-43) in stem cells preconditioned with insulin-like growth factor-1 (IGF-1) is cytoprotective and reprograms the cells for cardiomyogenic differentiation.Sca-1+ cells were preconditioned with 100 nmol/L IGF-1 for 30 minutes followed by 8 hours of oxygen glucose deprivation to assess the cytoprotective effects of preconditioning. LDH release assay, cytochrome c release, and mitochondrial membrane potential assay showed improved survival of preconditioned Sca-1+ cells under oxygen glucose deprivation compared with nonpreconditioned Sca-1+ cells via PI3K/Akt-dependent caspase-3 downregulation. We observed PI3K/Akt-dependent upregulation of cardiac-specific markers including MEF-2c (2.5-fold), GATA4 (3.1-fold), and Cx-43 (3.5-fold). Cx-43 inhibition with specific RNA interference reduced cell survival under oxygen glucose deprivation and after transplantation. In vivo studies were performed in a female rat model of acute myocardial infarction (n=78). Animals were grouped to receive intramyocardially 70 microL Dulbecco modified Eagles medium without cells (group 1) or containing male 1 x 10(6) nonpreconditioned Sca-1+ cells (group 2) or preconditioned Sca-1+ (group 3) cells labeled with PKH26. Survival of the preconditioned Sca-1+ cells was 5.5-fold higher in group 3 compared with group 2 at 7 days after transplantation. Confocal imaging after actinin and Cx-43 specific immunostaining showed extensive engraftment and myogenic differentiation of preconditioned Sca-1+ cells. Compared with group 2, group 3 showed increased blood vessel density (22.3+/-1.7 per microscopic field; P<0.0001) and attenuated infarction size (23.3+/-3.6%; P=0.002). Heart function indices including ejection fraction (56.2+/-3.5; P=0.029) and fractional shortening (24.3+/-2.1; P=0.03) were improved in group 3 compared with group 2.Preconditioning with IGF-1 reprograms Sca-1+ for prosurvival signaling and cardiomyogenic differentiation with an important role for Cx-43 in this process.

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A central role of connexin 43 in hypoxic preconditioning.

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A central role of connexin 43 in hypoxic preconditioning.

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