Annarita di Lorenzo
Weill Cornell Medical College, USA
Nogo-A downregulation of ceramide de novo biosynthesis in cardiomyocytes protect the heart from failure
Altered sphingolipid levels correlate with heart failure. Recently, we identified Nogo-B, a membrane protein of the endoplasmic reticulum and highly expressed in blood vessels, as negative regulator of sphingolipid de novo biosynthesis, via serine palmitoyltransferase (SPT). In addition to Nogo-B, Reticulon-4 gene gives rise to splicing isoform Nogo-A transiently expressed in cardiomyocyte (CM) following pressure overload.
In this study we hypothesized that Nogo-A downregulates SPT activity in cardiomyocytes to impact heart failure.
To this end, mice lacking Nogo-A/B specifically in CM and controls received the transverse aortic constriction (TAC) to induce pressure overload in the left ventricle. The loss of Nogo-A in CM dramatically exacerbates pathological cardiac hypertrophy and dysfunction, resulting in survival rate reduction to ~50% at 3 months post-TAC. In absence of Nogo-A, SPT activity is significantly upregulated in CM at 7 days post-TAC, and correlates with the increased ceramide levels. Mechanistically, elevated ceramides lead to suppression of autophagy and severe heart failure.
In conclusion, we discovered Nogo-A as a key regulator of SPT activity in cardiomyocytes when exposed to hemodynamic stress. In this condition, Nogo-A limits ceramide accrual, therefore the onset of pathological cardiac hypertrophy, by preserving the “beneficial” autophagy.