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A soluble receptor for advanced glycation end-products inhibits hypoxia/reoxygenation-induced apoptosis in rat cardiomyocytes via the mitochondrial pathway.

Guo C, Zeng X, Song J, Zhang M, Wang H, Xu X, Du F, Chen B - Int J Mol Sci (2012)

Bottom Line: Compared with H/R alone, sRAGE pretreatment reduced H/R-induced cardiomyocyte apoptosis from 27.9% ± 5.9% to 9.4% ± 0.7% (p < 0.05).In addition, sRAGE treatment significantly inhibited H/R-induced mitochondrial depolarization and mPTP opening, reduced mitochondrial cytochrome c leakage, caspase-3 and caspase-9 activity, and decreased the ratio of Bax to Bcl-2.Therefore, we conclude that the exogenous administration of sRAGE during H/R is involved in cardioprotection by inhibiting apoptosis via the mitochondrial pathway, which, if further confirmed in vivo, may have important clinical implications during H/R.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China; E-Mails: songjuan2008@163.com (J.S.); dayanjingzm@sina.com (M.Z.); xuxiaoweittyy@sina.com (X.X.); fhduu@yahoo.com.cn (F.D.); chbux@126.com (B.C.).

ABSTRACT
Severe myocardial dysfunction and tissue damage resulting from ischemia/reperfusion (I/R) is a common clinical scenario in patients with certain types of heart diseases and therapies such as thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting, and cardiac transplantation. The underlining mechanism of endogenous cardiac protection after I/R injury has been a focus of current research. Growing evidences suggests that soluble receptor for advanced glycation end-products (sRAGE) has a cardioprotective effect; however, its role in I/R injury remains unclear. We hypothesized that exogenous administration of sRAGE during hypoxia/reoxygenation (H/R) induces cardioprotection by inhibiting cardiomyocyte apoptosis via multiple signals, involving mitochondrial membrane potential (MMP), the mitochondrial permeability transition pore (mPTP), mitochondrial cytochrome c, caspase-3, Bcl-2 and Bax. Neonatal rat cardiomyocytes underwent hypoxia for 3-h followed by 2-h reoxygenation or were treated with sRAGE for 10 min before H/R. Compared with H/R alone, sRAGE pretreatment reduced H/R-induced cardiomyocyte apoptosis from 27.9% ± 5.9% to 9.4% ± 0.7% (p < 0.05). In addition, sRAGE treatment significantly inhibited H/R-induced mitochondrial depolarization and mPTP opening, reduced mitochondrial cytochrome c leakage, caspase-3 and caspase-9 activity, and decreased the ratio of Bax to Bcl-2. Therefore, we conclude that the exogenous administration of sRAGE during H/R is involved in cardioprotection by inhibiting apoptosis via the mitochondrial pathway, which, if further confirmed in vivo, may have important clinical implications during H/R.

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Effect of sRAGE on the ratio of Bax to Bcl-2. (A) Western blot analysis of Bax and Bcl-2 (upper panels) and β-actin (loading control; lower panel). (B) Densitometry of Bax and Bcl-2 levels normalized to β-actin in each treatment condition in (A). Dose of sRAGE was 900 ng/mL. Data are the mean ± SD (* p < 0.01 vs. control. # p < 0.01 vs. H/R; n = 4).
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f7-ijms-13-11923: Effect of sRAGE on the ratio of Bax to Bcl-2. (A) Western blot analysis of Bax and Bcl-2 (upper panels) and β-actin (loading control; lower panel). (B) Densitometry of Bax and Bcl-2 levels normalized to β-actin in each treatment condition in (A). Dose of sRAGE was 900 ng/mL. Data are the mean ± SD (* p < 0.01 vs. control. # p < 0.01 vs. H/R; n = 4).

Mentions: The Bcl-2 family proteins Bax and Bcl-2 play important roles in initiating the mitochondrial death cascade. Western blot analysis was used to investigate the expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 underlying apoptosis reduced by sRAGE. Compared with the control group, H/R significantly increased the ratio of Bax to Bcl-2 by 130% (2.30 ± 0.41, n = 4, p < 0.01) (Figure 7). Compared with H/R, sRAGE significantly decreased the H/R-induced increase in ratio of Bax to Bcl-2 from 2.30 ± 0.41 to 1.40 ± 0.14 (n = 4, p < 0.01). sRAGE alone had no effect on the ratio of Bax to Bcl-2. Thus, sRAGE inhibited apoptosis induced by H/R through increasing the ratio of Bax to Bcl-2.


A soluble receptor for advanced glycation end-products inhibits hypoxia/reoxygenation-induced apoptosis in rat cardiomyocytes via the mitochondrial pathway.

Guo C, Zeng X, Song J, Zhang M, Wang H, Xu X, Du F, Chen B - Int J Mol Sci (2012)

Effect of sRAGE on the ratio of Bax to Bcl-2. (A) Western blot analysis of Bax and Bcl-2 (upper panels) and β-actin (loading control; lower panel). (B) Densitometry of Bax and Bcl-2 levels normalized to β-actin in each treatment condition in (A). Dose of sRAGE was 900 ng/mL. Data are the mean ± SD (* p < 0.01 vs. control. # p < 0.01 vs. H/R; n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472784&req=5

f7-ijms-13-11923: Effect of sRAGE on the ratio of Bax to Bcl-2. (A) Western blot analysis of Bax and Bcl-2 (upper panels) and β-actin (loading control; lower panel). (B) Densitometry of Bax and Bcl-2 levels normalized to β-actin in each treatment condition in (A). Dose of sRAGE was 900 ng/mL. Data are the mean ± SD (* p < 0.01 vs. control. # p < 0.01 vs. H/R; n = 4).
Mentions: The Bcl-2 family proteins Bax and Bcl-2 play important roles in initiating the mitochondrial death cascade. Western blot analysis was used to investigate the expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 underlying apoptosis reduced by sRAGE. Compared with the control group, H/R significantly increased the ratio of Bax to Bcl-2 by 130% (2.30 ± 0.41, n = 4, p < 0.01) (Figure 7). Compared with H/R, sRAGE significantly decreased the H/R-induced increase in ratio of Bax to Bcl-2 from 2.30 ± 0.41 to 1.40 ± 0.14 (n = 4, p < 0.01). sRAGE alone had no effect on the ratio of Bax to Bcl-2. Thus, sRAGE inhibited apoptosis induced by H/R through increasing the ratio of Bax to Bcl-2.

Bottom Line: Compared with H/R alone, sRAGE pretreatment reduced H/R-induced cardiomyocyte apoptosis from 27.9% ± 5.9% to 9.4% ± 0.7% (p < 0.05).In addition, sRAGE treatment significantly inhibited H/R-induced mitochondrial depolarization and mPTP opening, reduced mitochondrial cytochrome c leakage, caspase-3 and caspase-9 activity, and decreased the ratio of Bax to Bcl-2.Therefore, we conclude that the exogenous administration of sRAGE during H/R is involved in cardioprotection by inhibiting apoptosis via the mitochondrial pathway, which, if further confirmed in vivo, may have important clinical implications during H/R.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China; E-Mails: songjuan2008@163.com (J.S.); dayanjingzm@sina.com (M.Z.); xuxiaoweittyy@sina.com (X.X.); fhduu@yahoo.com.cn (F.D.); chbux@126.com (B.C.).

ABSTRACT
Severe myocardial dysfunction and tissue damage resulting from ischemia/reperfusion (I/R) is a common clinical scenario in patients with certain types of heart diseases and therapies such as thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting, and cardiac transplantation. The underlining mechanism of endogenous cardiac protection after I/R injury has been a focus of current research. Growing evidences suggests that soluble receptor for advanced glycation end-products (sRAGE) has a cardioprotective effect; however, its role in I/R injury remains unclear. We hypothesized that exogenous administration of sRAGE during hypoxia/reoxygenation (H/R) induces cardioprotection by inhibiting cardiomyocyte apoptosis via multiple signals, involving mitochondrial membrane potential (MMP), the mitochondrial permeability transition pore (mPTP), mitochondrial cytochrome c, caspase-3, Bcl-2 and Bax. Neonatal rat cardiomyocytes underwent hypoxia for 3-h followed by 2-h reoxygenation or were treated with sRAGE for 10 min before H/R. Compared with H/R alone, sRAGE pretreatment reduced H/R-induced cardiomyocyte apoptosis from 27.9% ± 5.9% to 9.4% ± 0.7% (p < 0.05). In addition, sRAGE treatment significantly inhibited H/R-induced mitochondrial depolarization and mPTP opening, reduced mitochondrial cytochrome c leakage, caspase-3 and caspase-9 activity, and decreased the ratio of Bax to Bcl-2. Therefore, we conclude that the exogenous administration of sRAGE during H/R is involved in cardioprotection by inhibiting apoptosis via the mitochondrial pathway, which, if further confirmed in vivo, may have important clinical implications during H/R.

Show MeSH
Related in: MedlinePlus