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Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation.

Cavalheiro RA, Marin RM, Rocco SA, Cerqueira FM, da Silva CC, Rittner R, Kowaltowski AJ, Vercesi AE, Franchini KG, Castilho RF - PLoS ONE (2010)

Bottom Line: PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition.The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state.We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

ABSTRACT

Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function.

Methodology/principal findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation.

Conclusions/significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

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Related in: MedlinePlus

PD153035 protects against cardiac cell damage promoted by cyanide/aglycemia.Panel A: Cardiac HL-1 cells were preincubated in standard media (see Materials and Methods) containing 10 nM PD153035 (▴), the equivalent concentration of PD153035 solvent DMSO (0.05%; ▪) or no further additions (○, ⋄). Where indicated, all cells except controls (○) were treated with 10 mM K-cyanide (CN) and 2 mM 2-deoxyglucose (2-DG). All cells were submitted to equal centrifugations and media changes where indicated by the arrows. Panel B represents average cellular viability at 140 min. HL-1 cells were treated as described in Panel A. Where indicated, cells were preincubated in the presence of 60 µM 5-hydroxydecanoate (5HD) and/or 10 nM PD153035 (PD). Data represent average cell viability (see Materials and Methods) of 5 experiments±SEM. Data in Panels A and B represent separate experimental groups in which baseline measurements are not significantly distinct. *p<0.05 relative to “control” and “CN+2-DG+PD153035” at the respective time point. #p<0.05 relative to “CN+2-DG” at the respective time point.
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pone-0010666-g002: PD153035 protects against cardiac cell damage promoted by cyanide/aglycemia.Panel A: Cardiac HL-1 cells were preincubated in standard media (see Materials and Methods) containing 10 nM PD153035 (▴), the equivalent concentration of PD153035 solvent DMSO (0.05%; ▪) or no further additions (○, ⋄). Where indicated, all cells except controls (○) were treated with 10 mM K-cyanide (CN) and 2 mM 2-deoxyglucose (2-DG). All cells were submitted to equal centrifugations and media changes where indicated by the arrows. Panel B represents average cellular viability at 140 min. HL-1 cells were treated as described in Panel A. Where indicated, cells were preincubated in the presence of 60 µM 5-hydroxydecanoate (5HD) and/or 10 nM PD153035 (PD). Data represent average cell viability (see Materials and Methods) of 5 experiments±SEM. Data in Panels A and B represent separate experimental groups in which baseline measurements are not significantly distinct. *p<0.05 relative to “control” and “CN+2-DG+PD153035” at the respective time point. #p<0.05 relative to “CN+2-DG” at the respective time point.

Mentions: The cardioprotective effects of PD153035 were confirmed using a cultured cell model involving murine cardiac HL-1 cells, which allows for direct measurements of cell death [14], [31]. In these cells, metabolic inhibition promoted by treatment with cyanide and 2-deoxyglucose, followed by return to control conditions, mimics cardiac ischemia/reperfusion (Figure 2A, ⋄). Indeed, cell death occurs predominantly after the return of metabolic activity (the simulated reperfusion period which begins where indicated by the second arrow) [14]. The presence of 10 nM PD153035 in the preincubation media completely abrogated cell death promoted by cyanide/aglycemia in cardiac HL-1 cells (▴), while an equal quantity of the compound's solvent, DMSO (0.05%), had no protective effect (▪).


Potent cardioprotective effect of the 4-anilinoquinazoline derivative PD153035: involvement of mitochondrial K(ATP) channel activation.

Cavalheiro RA, Marin RM, Rocco SA, Cerqueira FM, da Silva CC, Rittner R, Kowaltowski AJ, Vercesi AE, Franchini KG, Castilho RF - PLoS ONE (2010)

PD153035 protects against cardiac cell damage promoted by cyanide/aglycemia.Panel A: Cardiac HL-1 cells were preincubated in standard media (see Materials and Methods) containing 10 nM PD153035 (▴), the equivalent concentration of PD153035 solvent DMSO (0.05%; ▪) or no further additions (○, ⋄). Where indicated, all cells except controls (○) were treated with 10 mM K-cyanide (CN) and 2 mM 2-deoxyglucose (2-DG). All cells were submitted to equal centrifugations and media changes where indicated by the arrows. Panel B represents average cellular viability at 140 min. HL-1 cells were treated as described in Panel A. Where indicated, cells were preincubated in the presence of 60 µM 5-hydroxydecanoate (5HD) and/or 10 nM PD153035 (PD). Data represent average cell viability (see Materials and Methods) of 5 experiments±SEM. Data in Panels A and B represent separate experimental groups in which baseline measurements are not significantly distinct. *p<0.05 relative to “control” and “CN+2-DG+PD153035” at the respective time point. #p<0.05 relative to “CN+2-DG” at the respective time point.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2871796&req=5

pone-0010666-g002: PD153035 protects against cardiac cell damage promoted by cyanide/aglycemia.Panel A: Cardiac HL-1 cells were preincubated in standard media (see Materials and Methods) containing 10 nM PD153035 (▴), the equivalent concentration of PD153035 solvent DMSO (0.05%; ▪) or no further additions (○, ⋄). Where indicated, all cells except controls (○) were treated with 10 mM K-cyanide (CN) and 2 mM 2-deoxyglucose (2-DG). All cells were submitted to equal centrifugations and media changes where indicated by the arrows. Panel B represents average cellular viability at 140 min. HL-1 cells were treated as described in Panel A. Where indicated, cells were preincubated in the presence of 60 µM 5-hydroxydecanoate (5HD) and/or 10 nM PD153035 (PD). Data represent average cell viability (see Materials and Methods) of 5 experiments±SEM. Data in Panels A and B represent separate experimental groups in which baseline measurements are not significantly distinct. *p<0.05 relative to “control” and “CN+2-DG+PD153035” at the respective time point. #p<0.05 relative to “CN+2-DG” at the respective time point.
Mentions: The cardioprotective effects of PD153035 were confirmed using a cultured cell model involving murine cardiac HL-1 cells, which allows for direct measurements of cell death [14], [31]. In these cells, metabolic inhibition promoted by treatment with cyanide and 2-deoxyglucose, followed by return to control conditions, mimics cardiac ischemia/reperfusion (Figure 2A, ⋄). Indeed, cell death occurs predominantly after the return of metabolic activity (the simulated reperfusion period which begins where indicated by the second arrow) [14]. The presence of 10 nM PD153035 in the preincubation media completely abrogated cell death promoted by cyanide/aglycemia in cardiac HL-1 cells (▴), while an equal quantity of the compound's solvent, DMSO (0.05%), had no protective effect (▪).

Bottom Line: PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition.The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state.We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil.

ABSTRACT

Background: The aim of the present study was to evaluate the protective effects of the 4-anilinoquinazoline derivative PD153035 on cardiac ischemia/reperfusion and mitochondrial function.

Methodology/principal findings: Perfused rat hearts and cardiac HL-1 cells were used to determine cardioprotective effects of PD153035. Isolated rat heart mitochondria were studied to uncover mechanisms of cardioprotection. Nanomolar doses of PD153035 strongly protect against heart and cardiomyocyte damage induced by ischemia/reperfusion and cyanide/aglycemia. PD153035 did not alter oxidative phosphorylation, nor directly prevent Ca(2+) induced mitochondrial membrane permeability transition. The protective effect of PD153035 on HL-1 cells was also independent of AKT phosphorylation state. Interestingly, PD153035 activated K(+) transport in isolated mitochondria, in a manner prevented by ATP and 5-hydroxydecanoate, inhibitors of mitochondrial ATP-sensitive K(+) channels (mitoK(ATP)). 5-Hydroxydecanoate also inhibited the cardioprotective effect of PD153035 in cardiac HL-1 cells, demonstrating that this protection is dependent on mitoK(ATP) activation.

Conclusions/significance: We conclude that PD153035 is a potent cardioprotective compound and acts in a mechanism involving mitoK(ATP) activation.

Show MeSH
Related in: MedlinePlus