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Cardiac microvascular barrier function mediates the protection of Tongxinluo against myocardial ischemia/reperfusion injury.

Qi K, Li L, Li X, Zhao J, Wang Y, You S, Hu F, Zhang H, Cheng Y, Kang S, Cui H, Duan L, Jin C, Zheng Q, Yang Y - PLoS ONE (2015)

Bottom Line: Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively).Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI.Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.

ABSTRACT

Objective: Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network.

Materials and methods: To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed.

Results: Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI.

Conclusions: Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

No MeSH data available.


Related in: MedlinePlus

Levels of 9 key indices in different groups.Expression of SUR2, eNOS, VE-cadherin, β-, γ-catenin, P-selectin and activities of eNOS, iNOS and PKA were compared among sham, model, IPC, verapamil, diltiazem and TXL groups. **P<0.01 vs Sham; #P<0.05 vs Model; ##P<0.01 vs Model; ΔP<0.05 vs IPC; ΔΔP<0.01 vs IPC; ★★P<0.01 vs verapamil; ☆☆P<0.01 vs diltiazem.
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pone.0119846.g008: Levels of 9 key indices in different groups.Expression of SUR2, eNOS, VE-cadherin, β-, γ-catenin, P-selectin and activities of eNOS, iNOS and PKA were compared among sham, model, IPC, verapamil, diltiazem and TXL groups. **P<0.01 vs Sham; #P<0.05 vs Model; ##P<0.01 vs Model; ΔP<0.05 vs IPC; ΔΔP<0.01 vs IPC; ★★P<0.01 vs verapamil; ☆☆P<0.01 vs diltiazem.

Mentions: To confirm the role of these cardiac structure and function-related targets in mediating the protection of TXL against lethal IRI, the expression of these indices were compared among model, TXL, IPC and CCB groups. Our results show that TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group, indicating maintaining these indices may induce cardioprotection after reperfusion. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group, indicating activating these indices by TXL may strengthen I/R-induced intrinsic protective signaling pathway, including PKA and eNOS, which is in accordance with our previous studies [5,31]. Among the above nine key indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with CCB (all P<0.01). Furthermore, there was no significant difference for these five indices between TXL and IPC groups (all P>0.05) (Fig. 8). Therefore, these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. However, there was no significant difference for SUR2, iNOS activity and PKA activity between TXL and CCB (all P>0.05).


Cardiac microvascular barrier function mediates the protection of Tongxinluo against myocardial ischemia/reperfusion injury.

Qi K, Li L, Li X, Zhao J, Wang Y, You S, Hu F, Zhang H, Cheng Y, Kang S, Cui H, Duan L, Jin C, Zheng Q, Yang Y - PLoS ONE (2015)

Levels of 9 key indices in different groups.Expression of SUR2, eNOS, VE-cadherin, β-, γ-catenin, P-selectin and activities of eNOS, iNOS and PKA were compared among sham, model, IPC, verapamil, diltiazem and TXL groups. **P<0.01 vs Sham; #P<0.05 vs Model; ##P<0.01 vs Model; ΔP<0.05 vs IPC; ΔΔP<0.01 vs IPC; ★★P<0.01 vs verapamil; ☆☆P<0.01 vs diltiazem.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363146&req=5

pone.0119846.g008: Levels of 9 key indices in different groups.Expression of SUR2, eNOS, VE-cadherin, β-, γ-catenin, P-selectin and activities of eNOS, iNOS and PKA were compared among sham, model, IPC, verapamil, diltiazem and TXL groups. **P<0.01 vs Sham; #P<0.05 vs Model; ##P<0.01 vs Model; ΔP<0.05 vs IPC; ΔΔP<0.01 vs IPC; ★★P<0.01 vs verapamil; ☆☆P<0.01 vs diltiazem.
Mentions: To confirm the role of these cardiac structure and function-related targets in mediating the protection of TXL against lethal IRI, the expression of these indices were compared among model, TXL, IPC and CCB groups. Our results show that TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group, indicating maintaining these indices may induce cardioprotection after reperfusion. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group, indicating activating these indices by TXL may strengthen I/R-induced intrinsic protective signaling pathway, including PKA and eNOS, which is in accordance with our previous studies [5,31]. Among the above nine key indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with CCB (all P<0.01). Furthermore, there was no significant difference for these five indices between TXL and IPC groups (all P>0.05) (Fig. 8). Therefore, these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI. However, there was no significant difference for SUR2, iNOS activity and PKA activity between TXL and CCB (all P>0.05).

Bottom Line: Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively).Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI.Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.

ABSTRACT

Objective: Tongxinluo (TXL) has been shown to decrease myocardial necrosis after ischemia/reperfusion (I/R) by simulating ischemia preconditioning (IPC). However, the core mechanism of TXL remains unclear. This study was designed to investigate the key targets of TXL against I/R injury (IRI) among the cardiac structure-function network.

Materials and methods: To evaluate the severity of lethal IRI, a mathematical model was established according to the relationship between myocardial no-reflow size and necrosis size. A total of 168 mini-swine were employed in myocardial I/R experiment. IRI severity among different interventions was compared and IPC and CCB groups were identified as the mildest and severest groups, respectively. Principal component analysis was applied to further determine 9 key targets of IPC in cardioprotection. Then, the key targets of TXL in cardioprotection were confirmed.

Results: Necrosis size and no-reflow size fit well with the Sigmoid Emax model. Necrosis reduction space (NRS) positively correlates with I/R injury severity and necrosis size (R2=0.92, R2=0.57, P<0.01, respectively). Functional and structural indices correlate positively with NRS (R2=0.64, R2=0.62, P<0.01, respectively). TXL recovers SUR2, iNOS activity, eNOS activity, VE-cadherin, β-catenin, γ-catenin and P-selectin with a trend toward the sham group. Moreover, TXL increases PKA activity and eNOS expression with a trend away from the sham group. Among the above nine indices, eNOS activity, eNOS, VE-cadherin, β-catenin and γ-catenin expression were significantly up-regulated by TXL compared with IPC (P>0.05) or CCB (P<0.05) and these five microvascular barrier-related indices may be the key targets of TXL in minimizing IRI.

Conclusions: Our study underlines the lethal IRI as one of the causes of myocardial necrosis. Pretreatment with TXL ameliorates myocardial IRI through promoting cardiac microvascular endothelial barrier function by simulating IPC.

No MeSH data available.


Related in: MedlinePlus