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

Area of Science:

• Cardiovascular Biology
• Molecular Metabolism
• Cellular Stress Response

Background:

• Sphingolipid ceramide accumulation is linked to heart failure (HF).
• Regulation of cardiac sphingolipid metabolism and its pathological role are poorly understood.
• Nogo proteins, particularly Nogo-A, are implicated in cellular functions, but their cardiac role is unknown.

Purpose of the Study:

• To investigate the biological function of Nogo-A in cardiomyocytes (CM) under stress.
• To determine Nogo-A's role in regulating sphingolipid biosynthesis and ceramide levels in the heart.
• To elucidate the protective mechanisms of Nogo-A against cardiac dysfunction and heart failure.

Main Methods:

• Utilized a mouse model with pressure overload induced by transverse aortic constriction (TAC).
• Assessed serine palmitoyltransferase (SPT) activity, ceramide levels, autophagy, mitochondrial function, and gene expression in cardiomyocytes lacking Nogo-A.
• Evaluated cardiac hypertrophy, dysfunction, and survival rates in Nogo-A deficient mice post-TAC.

Main Results:

• Nogo-A deficiency in CM led to increased SPT activity and ceramide accrual, especially very long-chain ceramides, under haemodynamic stress.
• Lack of Nogo-A suppressed 'beneficial' autophagy and impaired mitochondrial function and metabolic gene expression.
• Mice lacking Nogo-A exhibited exacerbated cardiac hypertrophy, dysfunction, and a 50% mortality rate at 3 months post-TAC.

Conclusions:

• Nogo-A acts as a negative regulator of SPT activity, preventing ceramide de novo biosynthesis in CM under stress.
• Nogo-A preserves cardiac function by maintaining autophagy, mitochondrial integrity, and metabolic homeostasis, thereby limiting progression to heart failure.
• Targeting Nogo-A or sphingolipid metabolism may offer novel therapeutic strategies for heart failure.