Age-related Alteration of Gap Junction Distribution and Connexin Expression in Rat Aortic Endothelium

Yeh, Hung‐I; Chang, Hao-Min; Lu, Wenwei; Lee, Yi-Nan; Ko, Yousang; Severs, Nicholas J.; Tsai, Cheng‐Ho

doi:10.1177/002215540004801008

Cited by 73 publications

(58 citation statements)

References 49 publications

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“…An important finding in our study is that the expression of Cx43 protein in aged rats in SO group was markedly lower than that in adult rats, consistent with previous findings that Cx43 protein and mRNA levels are reduced with increasing age in various species and models and the reduction of Cx43 expression appears to be a common feature of aging cells (Yeh et al 2000;Muramatsu et al 2004;Boengler et al 2006Boengler et al , 2007. Since Cx43 protein is an important element for cardiac electrophysiological stability Gutstein et al 2001), reduced Cx43 expression may contribute to the high incidence of ventricular arrhythmias in aged individuals.…”

Section: Discussionsupporting

confidence: 92%

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

2011

Tohoku J. Exp. Med.

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Reduced vagal activity is associated with increased risk for life-threatening arrhythmia during myocardial ischemia (MI); conversely, the increase in vagal tone may provide protective effect against ventricular arrhythmias. In fact, vagal nerve stimulation (VNS) exerted an anti-arrhythmic effect by preserving connexin 43 (Cx43), a gap junction protein in ventricles, in a rat model of MI. We investigated the effects of VNS on ventricular tachyarrhythmia during acute MI and the expression of Cx43 in aged rats. Both adult (3-4 months) and aged (≥ 24 months) male rats were subjected to ischemia of 30 min. VNS was applied before ischemia either alone or in combination with atropine (0.5 mg/kg) or carbenoxolone, a gap junction inhibitor (10 mg/kg). During the 30-min ischemia, the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) was higher in aged rats compared with adult rats. VNS significantly suppressed VT and VF in adult rats and these effects were eliminated by atropine or carbenoxolone. In contrast, VNS did not suppress VT and VF in the aged rats. Moreover, ischemia did not change the expression levels of total Cx43 protein in adult and aged rat ventricles. However, the expression level of total Cx43 protein was two times lower in sham-operated aged rats than that in sham-operated adult rats. Thus, in aged rats, loss of anti-arrhythmic effect of VNS is associated with reduced expression of Cx43 protein. These findings suggest that Cx43 may be an important target for inhibiting ischemia-induced VT in adult patients but not in aged patients.

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Section: Discussionsupporting

confidence: 92%

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

2011

Tohoku J. Exp. Med.

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“…This finding also suggests that age-dependent compensatory mechanisms may be a factor in partially restoring communication in older animals. Interestingly, age-dependent changes in endothelial connexin expression and colocalization have been reported for rat aorta (Yeh et al, 2000). Expression of endothelial Cx37, for example, showed a downward trend with age, and the extent of colocalization of Cx37 and Cx40 declined with age (Yeh et al, 2000).…”

Section: Discussionmentioning

confidence: 90%

Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin37 or connexin40

Simon

McWhorter

2003

Journal of Cell Science

127

145

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Vascular endothelial cells are coupled by gap junctions that permit cell-to-cell transfer of small molecules, including signals that may be important for vasomotor responses. Connexin37 (Cx37) and connexin40 (Cx40) are the predominant gap-junction proteins present in mouse endothelium. We examined the effect of eliminating Cx37, Cx40, or both, on interendothelial communication in mouse aorta. Intercellular transfer of biocytin and[2-(4-nitro-2,1,3-benzoxadiazol-7-yl)aminoethyl]trimethylammonium (NBD-TMA)was used to assess gap-junction-mediated coupling. Ablation of Cx40 generally had a greater effect on dye-transfer than ablation of Cx37. The effect of Cx40 ablation on dye-transfer was age dependent. There was a 27-fold reduction in biocytin transfer in embryonic Cx40–/– aortic endothelium, a much larger change than in aortas of 6-7-week-old Cx40–/– animals, which showed a 3.5-fold reduction. By contrast, there was no reduction in biocytin transfer in embryonic Cx37–/– endothelium. Embryonic aortas lacking both Cx37 and Cx40 showed a complete loss of endothelial dye-transfer. Surprisingly,elimination of Cx40 resulted in up to a 17-fold drop in endothelial Cx37 on western blots, whereas deletion of Cx37 reduced endothelial Cx40 up to 4.2-fold. By contrast, in the medial layer, both Cx37 and Cx43 increased∼fourfold in Cx40–/– aortas. Declines in non-ablated endothelial connexins were not mediated by changes in connexin mRNA levels, suggesting a post-transcriptional effect. Our results indicate that Cx37 and Cx40 are the only functional connexins expressed in mouse aortic endothelium and are collectively crucial for endothelial communication. Furthermore, Cx37 and Cx40 are codependent on each other for optimal expression in vascular endothelium.

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“…Statuto et al (22) reported a progressive decrease of the expression of Cx43 and GJIC in replicative senescence of cultured HEL-299 fibroblasts and termed Cx43 as a biomarker of cell senescence. It also has been shown that the expression and function of Cx43 in astrocytic cells and aortic endothelium were age related, suggesting that Cx43 and GJIC may play a role in the process of cell aging (23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P < 0.05) but also increased the percentage of senescence-associated ␤-galactosidase (SA-␤-gal) stained cells and expression of p21 cip1 and p27 kip1 (P < 0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-␤-gal stained cells and p27 kip1 and p21 cip1 expression in GMC (P < 0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-␤-gal stained cells (P < 0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.

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Age-related Alteration of Gap Junction Distribution and Connexin Expression in Rat Aortic Endothelium

Cited by 73 publications

References 49 publications

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

Loss of Anti-Arrhythmic Effect of Vagal Nerve Stimulation on Ischemia-Induced Ventricular Tachyarrhythmia in Aged Rats

Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin37 or connexin40

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

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