Lactate-upregulation of lactate oxidation complex-related genes is blunted in left ventricle of myocardial infarcted rats

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.

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure

“…Although MCT4 exhibits low expression in most cell types, including cardiomyocytes (Bonen, 2001;Bisetto et al, 2019), it is frequently induced under pathological scenarios. In the heart, MCT4 expression has been shown to be induced during myocardial injury (Zhu et al, 2013;Gabriel-Costa et al, 2018) and in hearts perfused with lactate (Gabriel-Costa et al, 2015). Furthermore, knocking out CD147, a broadly expressed plasma membrane glycoprotein known to be necessary for MCT4 function and localization (Kirk et al, 2000), has been recently reported to attenuate heart injury after pulmonary embolism and chronic pressure overload (Lu et al, 2018;Suzuki et al, 2016).…”

MCT4-dependent lactate transport: a novel mechanism for cardiac energy metabolism injury and inflammation in type 2 diabetes mellitus

“…Typically, MCT4 expression remains low in most cell types, including myocardial cells. However, its expression is upregulated in response to myocardial damage or perfusion with lactate [29,30]. It has been reported that knocking out CD147, a widely expressed plasma membrane glycoprotein essential for MCT4 function and localization, can alleviate myocardial injury resulting from pulmonary embolism and chronic pressure overload [31,32].…”

Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury

“…While increased MCT4 may be an acutely adaptive response to heart injury, enhancing lactate efflux may actually be counterproductive as it facilitates increased LDH reaction flux thereby siphoning pyruvate away from oxidation and enabling higher rates of glycolytic flux through rapid regeneration of cytoplasmic NAD+. In support of this idea, MCT4 inhibition therapy in mouse models has been established to prevent cardiomyocyte hypertrophy, and attenuate cardiac injury following pulmonary embolism and chronic pressure overload 18, 37, 38 .…”