Ketone body oxidation increases cardiac endothelial cell proliferation

Abstract

Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, lowcarbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases.

Dietary regulation in health and disease

“… 262 A low-carbohydrate, high-fat KD elevated the levels of ketone bodies to stimulate the proliferation of cardiac endothelial cells and prevent heart hypertrophy. 263 Particularly, MD alters the microbial compositions and function to benefit cardiometabolic homoeostasis, 264 , 265 and reduce diverse cardiovascular events like atherosclerosis to prevent cardiovascular disease. 266 , 267 Altogether, dietary interventions partially mediate these cardiovascular complications.…”

Artifactual FA dimers mimic FAHFA signals in untargeted metabolomics pipelines

“…Detection of differentially abundant metabolites is useful i ) for directing further mechanistic studies or ii ) to initiate new approaches for diagnosis and staging disease progression. Here, we revealed the formation of FAHFA-mimicking FA dimers within a commonly used LC-MS untargeted metabolomics pipeline ( 20 , 21 , 22 , 23 , 24 , 25 , 26 ) in both human and mouse serum samples on HILIC and RP chromatography. Follow-up studies confirmed that i ) these FA dimer species were indeed formed in the analytical pipeline, ii ) they were not FAHFAs, and iii ) FAHFAs do not form artifactually in the analytical pipeline.…”

“…Samples were stored at −80°C and extracted just prior to the analysis using the protocol from Ivanisevic et al. ( 21 ) with modifications ( 21 , 25 , 26 ). For quality control, serum was spiked with ISs of d 8 -Phe, d 8 -Val, and 13 C 4 -βOHB (10 μM each in final extract), normally absent in the serum and ion intensity monitored along the batch analysis.…”

“…We performed an untargeted metabolomics experiment using a commonly applied hydrophilic interaction LC coupled to ESI MS (HILIC-ESI-MS) method ( 20 , 21 , 22 , 23 , 24 , 25 , 26 ) and observed that multiple signals matching m/z of several FAHFAs were detected in human serum extracts. MS/MS databases putatively identified multiple FAHFA signals in studied human serum such as PAHSA, as well as oleic acid ester of hydroxy stearic acid (OAHSA), and palmitic acid ester of palmitic acid (PAHPA).…”

The janus face of ketone bodies in hypertension

“…In addition to serving as an energy source, bOHB has been revealed to be an important signaling molecule in a range of extrahepatic tissues by acting on different receptors and channels, including Gpr109a, Gpr41, and potassium channels. Although bOHB biosynthesis is diminished in animal models of hypertension [22,32], bOHB does have potential as a novel antihypertensive therapy because of its ability to promote endothelial-dependent vasodilation [22] and proliferation [23]. However, the evidence for the blood pressure-lowering effects of ketogenic diets is not conclusive and may actually be contraindicated in hypertensive patients because of adverse side effects (e.g.…”