Abstract
Lactate modulates the expression of lactate oxidation complex (LOC)-related genes and cardiac blood flow under physiological conditions, but its modulatory role remains to be elucidated regarding pathological cardiac stress. The present study evaluated the effect of lactate on LOC-related genes expression and hemodynamics of hearts submitted to myocardial infarction (MI). Four weeks after MI or sham operation, isolated hearts of male Wistar rats were perfused for 60 min with Na+-lactate (20 mM). As expected, MI reduced cardiac contractility and relaxation with no changes in perfusion. The impaired cardiac hemodynamics were associated with increased reactive oxygen species (ROS) levels (Sham: 19.3±0.5 vs MI: 23.8±0.3 µM), NADPH oxidase (NOX) activity (Sham: 42.2±1.3 vs MI: 60.5±1.5 nmol·h−1·mg−1) and monocarboxylate transporter 1 (mct1) mRNA levels (Sham: 1.0±0.06 vs MI: 1.7±0.2 a.u.), but no changes in superoxide dismutase (SOD), catalase, NADH oxidase (NADox), and xanthine oxidase activities. Lactate perfusion in MI hearts had no additional effect on ROS levels, NADox, and NOX activity, however, it partially reduced mct1 mRNA expression (MI-Lactate 1.3±0.08 a.u.). Interestingly, lactate significantly decreased SOD (MI-Lactate: 54.5±4.2 µmol·mg−1·min−1) and catalase (MI: 1.1±0.1 nmol·mg−1·min−1) activities in MI. Collectively, our data suggest that under pathological stress, lactate lacks its ability to modulate the expression of cardiac LOC-related genes and the perfused pressure in hearts submitted to chronic MI. Together, these data contribute to elucidate the mechanisms involved in the pathogenesis of heart failure induced by MI.
Highlights
Lactate is a metabolic intermediary compound that links energy metabolism to different organs and tissues [1]
The main finding of the present study is that lactate lacks its modulatory role in the expression of lactate oxidation complex (LOC)-related genes and in the relaxation of coronary arteries in hearts submitted to chronic pathological stress, such as myocardial infarction (MI)
We have previously demonstrated in healthy isolated hearts that lactate induced a slight, but significant increase in reactive oxygen species (ROS) production that was mainly associated with NADH oxidase (NADox) activity, nrf-2 nuclear expression, and LOC gene expression [5]
Summary
Lactate is a metabolic intermediary compound that links energy metabolism to different organs and tissues [1]. We and others have demonstrated that lactate modulates the expression of lactate oxidation complex (LOC)-related genes in both cardiac and skeletal muscle cells, which drive its usage as substrate fuel [5,6]. Lactate modulation of LOC-related genes occurs through the activation of redox-sensitive signaling pathways since lactate increases reactive oxygen species (ROS) levels and nuclear expression of the nuclear factor erythroid 2-related factor 2 (NRF-2), a redox-sensitive transcription factor [5,6]. Lactate modulates redox homeostasis in cardiac tissue by increasing the levels of reduced b-nicotinamide adenine dinucleotide (NADH) mainly due to the conversion of lactate to pyruvate by lactate dehydrogenase (LDH), which further activates a specific oxidase (NADH oxidase, NADox) leading to ROS production. We have observed that lactate perfusion reduces cardiac perfusion pressure in healthy isolated hearts [5]
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