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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

Relationship between no-reflow size and necrosis size.Myocardial necrosis size and no-reflow size fit a Sigmoid Emax model well. Myocardial necrosis size enlarges with the increase of no-reflow size. Abbreviations: IPC = ischemia preconditioning.
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pone.0119846.g002: Relationship between no-reflow size and necrosis size.Myocardial necrosis size and no-reflow size fit a Sigmoid Emax model well. Myocardial necrosis size enlarges with the increase of no-reflow size. Abbreviations: IPC = ischemia preconditioning.

Mentions: Sigmoid Emax is the classic model in pharmacodynamics, demonstrating the dose-effect relationship. Interestingly, our study showed that scatter points of no-reflow size (dose) and necrosis size (effect) fit well in a Sigmoid Emax model (Fig. 2, Formula 1). When the no-reflow size is 0%, the necrosis size is 0%. As the no-reflow size increases, the necrosis size elevates. When the no-reflow size continues to increase, the increase of necrosis size slows down, i.e. the necrosis size approaches a plateau. When the no-reflow size is 100%, the necrosis size is 100%. The model was selected according to the distribution character of data. Model parameters were obtained by the NONMEM method (S1 Table). EAN is the estimate of necrosis size. EANR is the observational no-reflow size. Emax is the largest necrosis size (Emax = 100%). EC50 is the no-reflow size when estimate of necrosis size is equal to 50% (EAN = 50%). r is the slope factor. ISV is the variation among trials. ε is the individual residual.


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)

Relationship between no-reflow size and necrosis size.Myocardial necrosis size and no-reflow size fit a Sigmoid Emax model well. Myocardial necrosis size enlarges with the increase of no-reflow size. Abbreviations: IPC = ischemia preconditioning.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119846.g002: Relationship between no-reflow size and necrosis size.Myocardial necrosis size and no-reflow size fit a Sigmoid Emax model well. Myocardial necrosis size enlarges with the increase of no-reflow size. Abbreviations: IPC = ischemia preconditioning.
Mentions: Sigmoid Emax is the classic model in pharmacodynamics, demonstrating the dose-effect relationship. Interestingly, our study showed that scatter points of no-reflow size (dose) and necrosis size (effect) fit well in a Sigmoid Emax model (Fig. 2, Formula 1). When the no-reflow size is 0%, the necrosis size is 0%. As the no-reflow size increases, the necrosis size elevates. When the no-reflow size continues to increase, the increase of necrosis size slows down, i.e. the necrosis size approaches a plateau. When the no-reflow size is 100%, the necrosis size is 100%. The model was selected according to the distribution character of data. Model parameters were obtained by the NONMEM method (S1 Table). EAN is the estimate of necrosis size. EANR is the observational no-reflow size. Emax is the largest necrosis size (Emax = 100%). EC50 is the no-reflow size when estimate of necrosis size is equal to 50% (EAN = 50%). r is the slope factor. ISV is the variation among trials. ε is the individual residual.

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