Pivotal role of membrane substrate transporters on the metabolic alterations in the pressure-overloaded heart

• Published in: Cardiovascular research 2019-05, Vol.115 (6), p.1000-1012
• Main Authors: Geraets, Ilvy M E, Glatz, Jan F C, Luiken, Joost J F P, Nabben, Miranda
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological; Animals; Aortic Valve Stenosis - complications; Aortic Valve Stenosis - physiopathology; Cardiomegaly - etiology; Cardiomegaly - metabolism; Cardiomegaly - physiopathology; Energy Metabolism; Heart Failure - etiology; Heart Failure - metabolism; Heart Failure - physiopathology; Hemodynamics; Humans; Hypertension - complications; Hypertension - physiopathology; Membrane Transport Proteins - metabolism; Myocytes, Cardiac - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvz060

Graphical Abstract Graphical Abstract Abstract Cardiac pressure overload (PO), such as caused by aortic stenosis and systemic hypertension, commonly results in cardiac hypertrophy and may lead to the development of heart failure. PO-induced heart failure is among the leading causes of death worldwide, but its pathological origin remains poorly understood. Metabolic alterations are proposed to be an important contributor to PO-induced cardiac hypertrophy and failure. While the healthy adult heart mainly uses long-chain fatty acids (FAs) and glucose as substrates for energy metabolism and to a lesser extent alternative substrates, i.e. lactate, ketone bodies, and amino acids (AAs), the pressure-overloaded heart is characterized by a shift in energy metabolism towards a greater reliance on glycolysis and alternative substrates. A key-governing kinetic step of both FA and glucose fluxes is at the level of their substrate-specific membrane transporters. The relative presence of these transporters in the sarcolemma determines the cardiac substrate preference. Whether the cardiac utilization of alternative substrates is also governed by membrane transporters is not yet known. In this review, we discuss current insight into the role of membrane substrate transporters in the metabolic alterations occurring in the pressure-overloaded heart. Given the increasing evidence of a role for alternative substrates in these metabolic alterations, there is an urgent need to disclose the key-governing kinetic steps in their utilization as well. Taken together, membrane substrate transporters emerge as novel targets for metabolic interventions to prevent or treat PO-induced heart failure.