Membrane Substrate Transporters as Target to Re‐balance Cardiac Energy Metabolism to Mend the Failing Heart

Abstract

BackgroundThere is growing recognition of the importance of energy metabolism in the cardiovascular system, and that disturbances therein are at the basis of causing cardiac disease. Specifically, chronic fuel shifts towards a single type of substrate are known to induce cardiac dysfunction. For instance, lipid overload due to Western life style or obesity eventually elicits diabetic cardiomyopathy, while excess glucose utilization is associated with hypertrophic heart failure (and vice versa). Therefore, interventions aimed at re‐balancing a tilted substrate preference toward an appropriate mix of substrates (in particular fatty acids and glucose) may result in restoration of cardiac contractile performance. Because the key‐governing kinetic step of substrate utilization is their sarcolemmal transport, we hypothesize that manipulating their recruitment to the sarcolemma is an effective approach to mend the failing heart.ResultsInhibition of the vesicular translocation of the fatty acid transporter CD36 to the sarcolemma by targeting endosomal H+‐ATPase in rat cardiomyocytes subjected to lipid overload completely restored both the fatty acid–glucose fuel balance and contractile function. Likewise, decreasing GLUT4‐mediated glucose uptake in experimental cardiac hypertrophy restored both the fuel balance and contractile function.ConclusionRe‐balancing cellular fuel supply, in particular with respect to fatty acids and glucose, appears an effective strategy to treat the failing heart. For such metabolic modulation therapy membrane substrate transporters, especially their subcellular recycling, are a promising target. Because vesicular trafficking involves >50 proteins and is highly (tissue‐)specific, manipulating transporter recycling would allow a heart‐specific approach.Support or Funding InformationMN is supported by the Dutch Heart Foundation, grant 2019T041.