Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure
| Autor: | Linda Sasset, Onorina Laura Manzo, Yi Zhang, Alice Marino, Luisa Rubinelli, Maria Antonietta Riemma, Madhavi Latha S Chalasani, Dragos C Dasoveanu, Fiorentina Roviezzo, Stanislovas S Jankauskas, Gaetano Santulli, Maria Rosaria Bucci, Theresa T Lu, Annarita Di Lorenzo |
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| Přispěvatelé: | Sasset, Linda, Manzo, Onorina Laura, Zhang, Yi, Marino, Alice, Rubinelli, Luisa, Riemma, Maria Antonietta, Chalasani, Madhavi Latha S, Dasoveanu, Dragos C, Roviezzo, Fiorentina, Jankauskas, Stanislovas S, Santulli, Gaetano, Bucci, Maria Rosaria, Lu, Theresa T, Di Lorenzo, Annarita, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Cardiovascular research, (2022) |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | Aims Growing evidence correlate the accrual of the sphingolipid ceramide in plasma and cardiac tissue with heart failure (HF). Regulation of sphingolipid metabolism in the heart and the pathological impact of its derangement remain poorly understood. Recently, we discovered that Nogo-B, a membrane protein of endoplasmic reticulum, abundant in the vascular wall, down-regulates the sphingolipid de novo biosynthesis via serine palmitoyltransferase (SPT), first and rate liming enzyme, to impact vascular functions and blood pressure. Nogo-A, a splice isoform of Nogo, is transiently expressed in cardiomyocyte (CM) following pressure overload. Cardiac Nogo is up-regulated in dilated and ischaemic cardiomyopathies in animals and humans. However, its biological function in the heart remains unknown. Methods and results We discovered that Nogo-A is a negative regulator of SPT activity and refrains ceramide de novo biosynthesis in CM exposed to haemodynamic stress, hence limiting ceramide accrual. At 7 days following transverse aortic constriction (TAC), SPT activity was significantly up-regulated in CM lacking Nogo-A and correlated with ceramide accrual, particularly very long-chain ceramides, which are the most abundant in CM, resulting in the suppression of ‘beneficial’ autophagy. At 3 months post-TAC, mice lacking Nogo-A in CM showed worse pathological cardiac hypertrophy and dysfunction, with ca. 50% mortality rate. Conclusion Mechanistically, Nogo-A refrains ceramides from accrual, therefore preserves the ‘beneficial’ autophagy, mitochondrial function, and metabolic gene expression, limiting the progression to HF under sustained stress. |
| Databáze: | OpenAIRE |
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