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Lactate up-regulates the expression of lactate oxidation complex-related genes in left ventricular cardiac tissue of rats.

Gabriel-Costa D, da Cunha TF, Bechara LR, Fortunato RS, Bozi LH, Coelho Mde A, Barreto-Chaves ML, Brum PC - PLoS ONE (2015)

Bottom Line: This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels.Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response.These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.

View Article: PubMed Central - PubMed

Affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.

ABSTRACT

Background: Besides its role as a fuel source in intermediary metabolism, lactate has been considered a signaling molecule modulating lactate-sensitive genes involved in the regulation of skeletal muscle metabolism. Even though the flux of lactate is significantly high in the heart, its role on regulation of cardiac genes regulating lactate oxidation has not been clarified yet. We tested the hypothesis that lactate would increase cardiac levels of reactive oxygen species and up-regulate the expression of genes related to lactate oxidation complex.

Methods/principal findings: Isolated hearts from male adult Wistar rats were perfused with control, lactate or acetate (20mM) added Krebs-Henseleit solution during 120 min in modified Langendorff apparatus. Reactive oxygen species (O2●-/H2O2) levels, and NADH and NADPH oxidase activities (in enriched microsomal or plasmatic membranes, respectively) were evaluated by fluorimetry while SOD and catalase activities were evaluated by spectrophotometry. mRNA levels of lactate oxidation complex and energetic enzymes MCT1, MCT4, HK, LDH, PDH, CS, PGC1α and COXIV were quantified by real time RT-PCR. Mitochondrial DNA levels were also evaluated. Hemodynamic parameters were acquired during the experiment. The key findings of this work were that lactate elevated cardiac NADH oxidase activity but not NADPH activity. This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels. Lactate increased NRF-2 nuclear expression and SOD activity probably as counter-regulatory responses to increased O2●-/H2O2.

Conclusions: Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response. These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.

No MeSH data available.


Hemodynamic parameters measured in perfused hearts.(A) Left ventricular developed pressure, (B) Heart rate, (C) +dP/dtmax, (D)-dP/dtmax and (E) Perfusion pressure after 120 min of perfusion with KH or KH + lactate (20mM) solutions. Values are mean ± SE of 10–15 hearts; *indicates p<0.05 vs. control group.
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pone.0127843.g005: Hemodynamic parameters measured in perfused hearts.(A) Left ventricular developed pressure, (B) Heart rate, (C) +dP/dtmax, (D)-dP/dtmax and (E) Perfusion pressure after 120 min of perfusion with KH or KH + lactate (20mM) solutions. Values are mean ± SE of 10–15 hearts; *indicates p<0.05 vs. control group.

Mentions: In order to verify whether lactate perfusion would change isolated heart function, we have assessed hemodynamic variables. As noted in Fig 5, no significant differences were observed in left ventricle developed pressure (Fig 5A), heart rate (Fig 5B), +dP/dt (Fig 5C),-dP/dt (Fig 5D). However, lactate perfusion significantly reduced PP values from 30 to 120 minutes (Fig 5E).


Lactate up-regulates the expression of lactate oxidation complex-related genes in left ventricular cardiac tissue of rats.

Gabriel-Costa D, da Cunha TF, Bechara LR, Fortunato RS, Bozi LH, Coelho Mde A, Barreto-Chaves ML, Brum PC - PLoS ONE (2015)

Hemodynamic parameters measured in perfused hearts.(A) Left ventricular developed pressure, (B) Heart rate, (C) +dP/dtmax, (D)-dP/dtmax and (E) Perfusion pressure after 120 min of perfusion with KH or KH + lactate (20mM) solutions. Values are mean ± SE of 10–15 hearts; *indicates p<0.05 vs. control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440754&req=5

pone.0127843.g005: Hemodynamic parameters measured in perfused hearts.(A) Left ventricular developed pressure, (B) Heart rate, (C) +dP/dtmax, (D)-dP/dtmax and (E) Perfusion pressure after 120 min of perfusion with KH or KH + lactate (20mM) solutions. Values are mean ± SE of 10–15 hearts; *indicates p<0.05 vs. control group.
Mentions: In order to verify whether lactate perfusion would change isolated heart function, we have assessed hemodynamic variables. As noted in Fig 5, no significant differences were observed in left ventricle developed pressure (Fig 5A), heart rate (Fig 5B), +dP/dt (Fig 5C),-dP/dt (Fig 5D). However, lactate perfusion significantly reduced PP values from 30 to 120 minutes (Fig 5E).

Bottom Line: This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels.Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response.These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.

View Article: PubMed Central - PubMed

Affiliation: School of physical Education and Sport, University of São Paulo, São Paulo, Brazil.

ABSTRACT

Background: Besides its role as a fuel source in intermediary metabolism, lactate has been considered a signaling molecule modulating lactate-sensitive genes involved in the regulation of skeletal muscle metabolism. Even though the flux of lactate is significantly high in the heart, its role on regulation of cardiac genes regulating lactate oxidation has not been clarified yet. We tested the hypothesis that lactate would increase cardiac levels of reactive oxygen species and up-regulate the expression of genes related to lactate oxidation complex.

Methods/principal findings: Isolated hearts from male adult Wistar rats were perfused with control, lactate or acetate (20mM) added Krebs-Henseleit solution during 120 min in modified Langendorff apparatus. Reactive oxygen species (O2●-/H2O2) levels, and NADH and NADPH oxidase activities (in enriched microsomal or plasmatic membranes, respectively) were evaluated by fluorimetry while SOD and catalase activities were evaluated by spectrophotometry. mRNA levels of lactate oxidation complex and energetic enzymes MCT1, MCT4, HK, LDH, PDH, CS, PGC1α and COXIV were quantified by real time RT-PCR. Mitochondrial DNA levels were also evaluated. Hemodynamic parameters were acquired during the experiment. The key findings of this work were that lactate elevated cardiac NADH oxidase activity but not NADPH activity. This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels. Lactate increased NRF-2 nuclear expression and SOD activity probably as counter-regulatory responses to increased O2●-/H2O2.

Conclusions: Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response. These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.

No MeSH data available.