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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 level of cleaved caspase-3. (A) Western blot analysis of cleaved caspase-3 (upper panel) and β-actin (loading control; lower panel); (B) Densitometry of cleaved caspase-3 normalized to β-actin in each treatment condition in (A); (C) Caspase-3 activity in lysates of cardiomyocytes; (D) Caspase-9 activity in lysates of cardiomyocytes. Data in (C) and (D) were expressed as percentage of control group. 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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f6-ijms-13-11923: Effect of sRAGE on the level of cleaved caspase-3. (A) Western blot analysis of cleaved caspase-3 (upper panel) and β-actin (loading control; lower panel); (B) Densitometry of cleaved caspase-3 normalized to β-actin in each treatment condition in (A); (C) Caspase-3 activity in lysates of cardiomyocytes; (D) Caspase-9 activity in lysates of cardiomyocytes. Data in (C) and (D) were expressed as percentage of control group. 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: Compared with the controls, H/R significantly increased the levels of cleaved caspase-3 by 57% (1.57 ± 0.13, n = 4, p < 0.01). sRAGE significantly attenuated the H/R-induced increase in cleaved caspase-3 from 1.10 ± 0.02 to 1.57 ± 0.13 (n = 4, p < 0.01). sRAGE alone had no effect on cleaved caspase-3 (Figure 6A,B). Compared with the controls, H/R significantly increased caspase-3 activity by 120% (2.20 ± 0.16, n = 4, p < 0.01). sRAGE significantly inhibited the H/R-induced increase in caspase-3 activity from 2.20 ± 0.16 to 1.30 ± 0.15 (n = 4, p < 0.01). sRAGE alone had no effect on caspase-3 activity (Figure 6C). Similar results appeared in caspase-9, compared with the controls, H/R significantly increased caspase-9 activity by 100% (2.00 ± 0.13, n = 4, p < 0.01). sRAGE significantly reduced the H/R-induced increase in caspase-9 activity from 2.00 ± 0.13 to 1.21 ± 0.19 (n = 4, p < 0.01). sRAGE alone had no effect on caspase-9 activity (Figure 6D). Therefore, sRAGE inhibits apoptosis by attenuating H/R-induced increase in caspase-3 and caspase-9 activity.


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 level of cleaved caspase-3. (A) Western blot analysis of cleaved caspase-3 (upper panel) and β-actin (loading control; lower panel); (B) Densitometry of cleaved caspase-3 normalized to β-actin in each treatment condition in (A); (C) Caspase-3 activity in lysates of cardiomyocytes; (D) Caspase-9 activity in lysates of cardiomyocytes. Data in (C) and (D) were expressed as percentage of control group. 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

f6-ijms-13-11923: Effect of sRAGE on the level of cleaved caspase-3. (A) Western blot analysis of cleaved caspase-3 (upper panel) and β-actin (loading control; lower panel); (B) Densitometry of cleaved caspase-3 normalized to β-actin in each treatment condition in (A); (C) Caspase-3 activity in lysates of cardiomyocytes; (D) Caspase-9 activity in lysates of cardiomyocytes. Data in (C) and (D) were expressed as percentage of control group. 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: Compared with the controls, H/R significantly increased the levels of cleaved caspase-3 by 57% (1.57 ± 0.13, n = 4, p < 0.01). sRAGE significantly attenuated the H/R-induced increase in cleaved caspase-3 from 1.10 ± 0.02 to 1.57 ± 0.13 (n = 4, p < 0.01). sRAGE alone had no effect on cleaved caspase-3 (Figure 6A,B). Compared with the controls, H/R significantly increased caspase-3 activity by 120% (2.20 ± 0.16, n = 4, p < 0.01). sRAGE significantly inhibited the H/R-induced increase in caspase-3 activity from 2.20 ± 0.16 to 1.30 ± 0.15 (n = 4, p < 0.01). sRAGE alone had no effect on caspase-3 activity (Figure 6C). Similar results appeared in caspase-9, compared with the controls, H/R significantly increased caspase-9 activity by 100% (2.00 ± 0.13, n = 4, p < 0.01). sRAGE significantly reduced the H/R-induced increase in caspase-9 activity from 2.00 ± 0.13 to 1.21 ± 0.19 (n = 4, p < 0.01). sRAGE alone had no effect on caspase-9 activity (Figure 6D). Therefore, sRAGE inhibits apoptosis by attenuating H/R-induced increase in caspase-3 and caspase-9 activity.

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