Top-NOTCH Regulation of Cardiac Metabolism

Article, see p 2592 The adult human heart is a fascinating organ. Despite weighing no more than 300 g (on average), it pumps 8 tons of blood through 60 000 miles of blood vessels each day. This remarkable performance is energetically demanding and consumes ≤10% of the body’s energy. However, the heart has little capacity for energy storage and thus relies on the continuous supply of exogenous metabolic resources. Under physiological conditions, the heart muscle uses fatty acids as a primary energy source. The muscle cells (cardiomyocytes) oxidize this energetic fuel in mitochondria to efficiently generate cellular energy in the form of ATP. Fatty acids are delivered to cardiomyocytes via a dense network of capillaries, whose interior is lined by a continuous layer of endothelial cells specialized for fatty acid transport.1 Unlike endothelial cells in many other vascular beds (eg, brain), these cells are rich in transporters and binding proteins that mediate the transcellular flux of blood-borne fatty acids to perivascular tissues (Figure, A). The importance of this tailored nutrient delivery is evident in disease. Indeed, a number of cardiomyopathies that lead to myocardial hypertrophy, dysfunction, and failure are associated with alterations in fatty acid utilization and cardiac energy metabolism.2 However, the mechanisms that regulate nutrient transfer in the heart are poorly understood. In this issue of Circulation , Jabs et al3 shed light on this question by reporting that endothelial Notch signaling critically regulates fatty acid transport capacity, thereby determining cardiac metabolism and function. These findings are interesting not only because of their medical implications, but also because they add to the emerging picture that organ-specific endothelial cells exert crucial gatekeeper functions that actively regulate and maintain tissue homeostasis.4 Figure. Regulation of nutrient transport in the heart by endothelial Notch signaling. A , Schematic illustration of …