Modulation of Perturbed Cardiac Metabolism in Rats Under High-Altitude Hypoxia by Combination Treatment With L-carnitine and Trimetazidine

Abstract

High-altitude hypoxia has long been recognized as a vital etiology for high-altitude illnesses. High-altitude myocardial injury (HAMI) usually occurs in people who suffered from high-altitude exposure. To date, the molecular mechanism of HAMI remains elusive, which seriously hinders the prevention and treatment of HAMI. L-carnitine and trimetazidine are classic cardiovascular protective medicines. In this study, we used the metabolomic method, based on GC/MS, to explore the changes in metabolites in rats exposed to high-altitude hypoxia and then illustrate the metabolic pathways associated with the modulatory effect of L-carnitine combined with trimetazidine on rats with high-altitude exposure. The results showed that metabolites in the myocardium in rats under high-altitude hypoxia were markedly changed, such as branched-chain amino acids (BCAA, leucine, isoleucine, and valine), taurine, succinic acid, fumaric acid, lactic acid, pyruvic acid, 3-hydroxybutyrate, and docosahexaenoic acid (DHA), while L-carnitine combined with trimetazidine modulated and improved the abnormal changes in energy substances caused by high-altitude hypoxia. L-carnitine mainly promoted the metabolism of fatty acids, while trimetazidine enhanced the glycolysis process. The combined administration of the two components not only increased the metabolism of fatty acids but also promoted aerobic glycolysis. Meanwhile, it contributed to the decrease in the elevation in some of the intermediates of the tricarboxylic acid (TCA) cycle, decrease in the production of 3-hydroxybutyric acid, and relief of the abnormal energy metabolism process in organisms and the cardiac tissue. Our analysis delineates the landscape of the metabolites in the myocardial tissue of rats that were exposed to high altitude. Moreover, L-carnitine combined with trimetazidine can relieve the HAMI through modulated and improved abnormal changes in energy substances caused by high-altitude hypoxia.

Chronic Hyperglycaemia Inhibits Tricarboxylic Acid Cycle in Rat Cardiomyoblasts Overexpressing Glucose Transporter Type 4

“…In the hypoxia model, the accumulation of several TCA compounds was detected by metabolomic analysis [26,27]. Whereas, particularly in the ischaemia model, the accumulation of succinate was described as a disease-specific signature, being responsible for mitochondrial ROS production during reperfusion [28].…”

The cardiovascular system at high altitude: A bibliometric and visualization analysis

“…Metabolomics at high altitude: Metabolomics is a promising tool for discovering and understanding the novel biochemical and metabolic responses to hypobaric hypoxia exposure; it can provide new insights for the field of medicine at high altitude and unravel the underlying mechanisms for the health problems that occur in subjects upon exposure to high altitude[ 75 ]. Xie et al [ 76 ] delineated the landscape of metabolites in the myocardial tissues of rats exposed to high altitude using GS/MS-based metabolomics and reported significant changes in metabolites, including several branched chain amino acids, taurine, succinic acid, and others[ 76 ]. Extensive evidence of metabolic reprogramming and phenotypic transformation of fetal sheep pulmonary arteries induced by chronic hypoxia has been revealed by metabolomics techniques, which may contribute to the development of persistent pulmonary hypertension[ 77 ].…”

Metabolic landscape in cardiac aging: insights into molecular biology and therapeutic implications

“…102 Moreover, β-HB suppresses mitochondrial dysfunction by disrupting NLPR3 inflammasome formation and antagonizing the proinflammatory SASP in aged mice. 298 In addition, both the pan carnitine O-palmitoyltransferase 1 (CPT1) inhibitor perhexiline 299,300 and the acetyl-CoA acyltransferase 2 inhibitor trimetazidine (TMZ) 301,302 are metabolic reprogramming modulators that have the ability to partially suppress mitochondrial free FA beta-oxidation partially, enhance glucose oxidation, and promote cardiac energetics (with an increased PCr:ATP ratio). The latter has been further suggested to halt cardiac aging as well as metabolic defects in animal models, 303,304 but there is a lack of clinical evidence and a very limited number of patient studies.…”