TY - JOUR
T1 - Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure
AU - Sasset, Linda
AU - Manzo, Onorina Laura
AU - Zhang, Yi
AU - Marino, Alice
AU - Rubinelli, Luisa
AU - Riemma, Maria Antonietta
AU - Chalasani, Madhavi Latha S.
AU - Dasoveanu, Dragos C.
AU - Roviezzo, Fiorentina
AU - Jankauskas, Stanislovas S.
AU - Santulli, Gaetano
AU - Bucci, Maria Rosaria
AU - Lu, Theresa T.
AU - Di Lorenzo, Annarita
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - Autophagy
KW - Ceramide
KW - Heart failure
KW - Mitochondrial function
KW - Sphingolipid metabolism
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U2 - 10.1093/cvr/cvac108
DO - 10.1093/cvr/cvac108
M3 - Article
C2 - 35815623
AN - SCOPUS:85151574950
SN - 0008-6363
VL - 119
SP - 506
EP - 519
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -