Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure.

TitleNogo-A reduces ceramide de novo biosynthesis to protect from heart failure.
Publication TypeJournal Article
Year of Publication2023
AuthorsSasset L, Manzo OLaura, Zhang Y, Marino A, Rubinelli L, Riemma MAntonietta, Chalasani MLatha S, Dasoveanu DC, Roviezzo F, Jankauskas SS, Santulli G, Bucci MRosaria, Lu TT, Di Lorenzo A
JournalCardiovasc Res
Volume119
Issue2
Pagination506-519
Date Published2023 Mar 31
ISSN1755-3245
KeywordsAnimals, Ceramides, Heart Failure, Humans, Mice, Myocytes, Cardiac, Nogo Proteins, Sphingolipids
Abstract

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.

DOI10.1093/cvr/cvac108
Alternate JournalCardiovasc Res
PubMed ID35815623
PubMed Central IDPMC10226746
Grant ListR01 AI079178 / AI / NIAID NIH HHS / United States
R01 HL126913 / HL / NHLBI NIH HHS / United States
R01 HL152195 / HL / NHLBI NIH HHS / United States
R21 AR081493 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Annarita Di Lorenzo, Ph.D.

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