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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 mitochondrial cytochrome c leakage. (A) Western blot analysis of mitochondrial cytochrome c protein (upper panel) and cytochrome oxidase IV (COXIV) (loading control; lower panel). Densitometry of cytochrome c levels normalized to COXIV in each treatment condition. Data are the mean ± SD (* p < 0.01 vs. control, # p < 0.01 vs. H/R; n = 4). (B) Western blot analysis of cytosolic cytochrome c protein (upper panel) and GAPDH (loading control; lower panel). Densitometry of cytochrome c levels normalized to GAPDH in each treatment condition. 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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f5-ijms-13-11923: Effect of sRAGE on mitochondrial cytochrome c leakage. (A) Western blot analysis of mitochondrial cytochrome c protein (upper panel) and cytochrome oxidase IV (COXIV) (loading control; lower panel). Densitometry of cytochrome c levels normalized to COXIV in each treatment condition. Data are the mean ± SD (* p < 0.01 vs. control, # p < 0.01 vs. H/R; n = 4). (B) Western blot analysis of cytosolic cytochrome c protein (upper panel) and GAPDH (loading control; lower panel). Densitometry of cytochrome c levels normalized to GAPDH in each treatment condition. 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: In the mitochondria-mediated apoptotic pathway, disruption of Δψm and release of cytochrome c activates a cascade of caspases, including caspase-3, a key and irreversible point in the development of apoptosis. Compared with the controls, H/R induced serious damage to the mitochondrial membranes, resulting in the release of cytochrome c from mitochondria. H/R significantly decreased cytochrome c in the mitochondria by 66% (0.34 ± 0.06, n = 4, p < 0.01). However, cytochrome c was significantly preserved in the H/R-sRAGE group. Compared with the H/R group, cytochrome c in the mitochondria in the H/R-sRAGE group increased from 0.34 ± 0.06 to 0.80 ± 0.08 (n = 4, p < 0.01). sRAGE alone had no effect on the release of cytochrome c (Figure 5). Few cytochrome c in the cytoplasm were found in the control group, while H/R significantly increased cytochrome c in the cytoplasm (0.55 ± 0.05, n = 4, p < 0.01). sRAGE pretreatment completely inhibited H/R-induced cytochrome c release into the cytoplasm.


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 mitochondrial cytochrome c leakage. (A) Western blot analysis of mitochondrial cytochrome c protein (upper panel) and cytochrome oxidase IV (COXIV) (loading control; lower panel). Densitometry of cytochrome c levels normalized to COXIV in each treatment condition. Data are the mean ± SD (* p < 0.01 vs. control, # p < 0.01 vs. H/R; n = 4). (B) Western blot analysis of cytosolic cytochrome c protein (upper panel) and GAPDH (loading control; lower panel). Densitometry of cytochrome c levels normalized to GAPDH in each treatment condition. 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

f5-ijms-13-11923: Effect of sRAGE on mitochondrial cytochrome c leakage. (A) Western blot analysis of mitochondrial cytochrome c protein (upper panel) and cytochrome oxidase IV (COXIV) (loading control; lower panel). Densitometry of cytochrome c levels normalized to COXIV in each treatment condition. Data are the mean ± SD (* p < 0.01 vs. control, # p < 0.01 vs. H/R; n = 4). (B) Western blot analysis of cytosolic cytochrome c protein (upper panel) and GAPDH (loading control; lower panel). Densitometry of cytochrome c levels normalized to GAPDH in each treatment condition. 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: In the mitochondria-mediated apoptotic pathway, disruption of Δψm and release of cytochrome c activates a cascade of caspases, including caspase-3, a key and irreversible point in the development of apoptosis. Compared with the controls, H/R induced serious damage to the mitochondrial membranes, resulting in the release of cytochrome c from mitochondria. H/R significantly decreased cytochrome c in the mitochondria by 66% (0.34 ± 0.06, n = 4, p < 0.01). However, cytochrome c was significantly preserved in the H/R-sRAGE group. Compared with the H/R group, cytochrome c in the mitochondria in the H/R-sRAGE group increased from 0.34 ± 0.06 to 0.80 ± 0.08 (n = 4, p < 0.01). sRAGE alone had no effect on the release of cytochrome c (Figure 5). Few cytochrome c in the cytoplasm were found in the control group, while H/R significantly increased cytochrome c in the cytoplasm (0.55 ± 0.05, n = 4, p < 0.01). sRAGE pretreatment completely inhibited H/R-induced cytochrome c release into the cytoplasm.

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