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Suppression of Endothelial Sphingolipid Metabolism and Signaling Contributes to Cardiometabolic Stress
Onorina Laura Manzo1, Jasmine Nour1,3, Sailesh Palikhe1, Martina Smimmo1,2, Luisa Rubinelli1, Alice Marino1, Yung Hu1, Olivier Elemento1, Julie K. Freed4, Giuseppe Danilo Norata3, Annarita Di Lorenzo1
1 Department of Pathology and Laboratory Medicine, Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
2 Department of Pharmacy, School of Medicine, University of Naples Federico II, via Domenico Montesano 49, Naples 80131, Italy.
3 Department of Excellence of Pharmacological and Biomolecular Sciences, University of Milan, Via G. Balzaretti, 9 - 20133, Milano, Italy.
4 Department of Anesthesiology, Medical College of Wisconsin Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd. Milwaukee, WI 53226, USA.
Background: Coronary artery diseases (CAD) remain the leading cause of death due to cardiovascular diseases. Endothelial cells (EC) form the inner layer of vessels and play a major role in maintaining vascular and cardiac homeostasis. Healthy endothelium preservers blood flow and fluidity, and refrains inflammation and platelet aggregation. Risk factors such as hypercholesterolemia, hypertension and diabetes set off endothelial dysfunction, an early event in the development of atherosclerosis.
Sphingolipids (SL) are building blocks for membranes and bioactive molecules. Although low-density lipoprotein cholesterol is the main measure of atherosclerotic risk, emerging clinical studies demonstrated a strong correlation between plasma sphingolipids, particularly sphingosine-1-phosphate (S1P) and ceramides, and CAD. Furthermore, specific ceramide species can predict major cardiovascular events. However, how sphingolipid levels change in the EC during CAD and contribute to dysfunction in vivo has never been investigated. SL are synthetized de novo in the membrane of the smooth ER, where serine palmitoyltransferase (SPT) catalyzes the first and rate-limiting step. Our lab discovered that the ER membrane protein Nogo-B, highly expressed in blood vessels, downregulates SPT activity, hence sphingolipid de novo production and signaling. This inhibitory brake of Nogo-B on SPT has critical pathological implications, contributing to endothelial dysfunction, inflammation,and hypertension.
Aims and Methods: Nogo-B is expressed in atherosclerotic lesions, particularly in the endothelium, of humans and mice. However, how Nogo-B regulation of sphingolipid metabolism and signaling impacts endothelial dysfunction in atherosclerosis is unknown.
To test the hypothesis that Nogo-B brake on SPT suppresses sphingolipid metabolism and signaling and contributes to endothelial dysfunction and CAD, we employed a novel mouse model of CAD recently developed in our lab. Transverse aortic constriction (TAC) exposes the heart to high pressure, and when combined with high cholesterol levels in ApoE-/- mice leads to coronary lesions recapitulating human CAD.
Results: Strikingly, ApoE-/- mice lacking Nogo-B in EC (ECKONogoA/B ApoE-/-) were resistant to coronary lesion formation in the left anterior descending artery (LAD) versus ApoE-/- mice at 8 weeks post-TAC. Specifically, the extend of coronary stenosis was ca. 50% reduced in absence of Nogo-B in the endothelium. Interestingly, cholesterol levels were no different between the two groups, suggesting a primary arterial-wall effect of Nogo-B. Consistently, cardiac function was significantly preserved in ECKONogoA/B ApoE-/- compared to ApoE -/-, with reduced mortality rate (ca. 50%). Interestingly, mice with coronary atherosclerosis showed the same changes in circulating S1P and ceramides observed in human affected by CAD. However, there was no difference between the two groups, suggesting that in mice the levels of ceramides did not correlate with the severity of the disease. Fibrous cap thickness, index of plaque vulnerability, was significantly higher in ECKONogoA/B ApoE-/- mice and correlated with diminished necrotic core area, and macrophage infiltration, suggesting that Nogo-B-mediated suppression of sphingolipid biosynthesis and signaling in the endothelium contributes to atherosclerosis development and progression. Mechanistically, in presence of hypercholesterolemia and high pressure, ECKONogoA/B ApoE-/- mice were protected from endothelial inflammatory and pro-atherosclerotic gene expression, as shown by the transcriptomic data.
Conclusions: In conclusions, our study is the first to demonstrate that Nogo-B-mediated suppression of sphingolipid de novo biosynthesis contributes to endothelial dysfunction and inflammation following hemodynamic stress and hypercholesterolemia, resulting in severe coronary atherosclerosis development and vulnerability in a novel mouse model of CAD.
This research was funded by R01 HL126913 from National Heart, Lung, and Blood Institute.
Speakers
Annarita Di Lorenzo