Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy

Abstract

The incidence of diabetes is increasing globally, with cardiovascular disease accounting for a substantial number of diabetes-related deaths. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, heart failure in patients with diabetes might also be an outcome of an intrinsic heart muscle malfunction, labelled diabetic cardiomyopathy. Changes in cardiomyocyte metabolism, which encompasses a shift to exclusive fatty acid utilization, are considered a leading stimulus for this cardiomyopathy. In addition to cardiomyocytes, endothelial cells (ECs) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. In this review, we will discuss the metabolic machinery that drives energy metabolism in the cardiomyocyte and EC, its breakdown following diabetes, and the research direction necessary to assist in devising novel therapeutic strategies to prevent or delay diabetic heart disease.

Keywords: Cardiomyocyte metabolism; Endothelial cell metabolism; Heparanase; Lipoprotein lipase; Vascular endothelial growth factor.

Figure 1

Cardiomyocyte metabolism. In the cardiomyocyte, two of the major substrates that are used for energy generation include glucose and FAs. Glucose uptake into the cardiomyocyte is predominantly a GLUT4 event. Following its entry into the cell, glucose can either be stored as glycogen or undergo glycolytic and oxidative metabolism to generate ATP. FA is the preferred energy substrate of the cardiomyocyte. Its entry is through a number of FA transporters including CD36, FAPB_PM, and FATP. FA can also undergo storage in the form of TGs or enter into the mitochondria to be oxidized for ATP.

Figure 2

EC metabolism. In the EC, glucose is the primary substrate used for energy generation. Upon entry using the GLUT1 transporter, glucose undergoes glycolysis—the pre-eminent metabolic pathway—to generate ATP. Under proliferative conditions, the EC shunts pyruvate, a metabolic intermediate of glycolysis, into the mitochondria to generate dNTP that is used for cell growth. Interesting, FAs are not typically used for energy generation in the EC, and instead, contribute to dNTP synthesis.

Figure 3

Cardiomyocyte–EC crosstalk. In the EC, latent heparanase is first secreted, followed by re-uptake and conversion to active heparanase. The secretion of both latent and active heparanase is dependent on glycolytically produced ATP. Both forms of heparanase are able to liberate myocyte surface-bound proteins including VEGFA and VEGFB. These growth factors have a paracrine influence on the EC, to facilitate angiogenesis through endothelial migration and proliferation. HSPG: heparan sulfate proteoglycan.

Figure 4

Synthesis and transport of LPL. Following gene transcription, LPL mRNA is translated to inactive LPL proteins. The inactive monomer undergoes glycosylation, and several other post-translational processes to be dimerized in the endoplasmic reticulum (ER). The fully processed LPL is sorted into vesicles that are targeted towards the cell surface for secretion. This process occurs by the movement along the actin cytoskeleton. Subsequently, it docks with the cell surface and releases LPL onto HSPG-binding sites on the plasma membrane. At the basolateral side of the EC, glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) captures LPL in the interstitial space and transfers it across to the apical side of the EC. GPIHBP1 functions as a platform to enable LPL to hydrolyse lipoprotein-TG and release FAs. More recent data suggest that EC can also synthesize LPL, albeit at a limited capacity.