Neutral sphingomyelinase in the mechanical regulation of the heart

ABSTRACT Degenerative cardiac remodeling from chronic overload is a significant contributor to cardiovascular disease. Signaling pathways initiated by pathologically elevated myocardial stretch are linked to multiple stretch-sensitive mechanisms, however, the signaling events that occur at the cell membrane to sense and transmit mechanical signals, at both physiological and pathological conditions, are still poorly understood. We identified neutral sphingomyelinase (nSMase), a membrane hydrolase enzyme involved in sphingolipid metabolism reactions, as a critical component of cardiac mechanosensing and mechano-chemical signal transduction. Our findings indicate that nSMase plays an important role in the regulation of normal physiological function of the heart upon acute changes in cardiac load, including autoregulatory chronotropic and inotropic responses. At the same time, chronic mechanical stress results in constitutively active nSMase increasing ceramide production and accumulation in damaged myocardium. It leads to deterioration of sarcolemmal membrane, elevated production of reactive oxygen species, blunted β-adrenergic response, and increased arrhythmogenesis, as also observed during chronic heart failure in patients and animal models of chronic cardiac overload. Moreover, mechanical and environmental stress is known to provoke certain genetically predisposed arrhythmogenic cardiomyopathy (ACM) to transition from quiescent to disease phenotype, yet no modulation methods or detection methods are available. These results position nSMase and associated signaling as key pathways for remodeling in heart failure and represent promising therapeutic options for mitigating the deleterious effects of cardiac pressure overload. However, there is limited research on nSMase in the heart. In this application, we will address this gap in knowledge and will determine the role of nSMase in mechanical regulation of cardiac function in both physiological conditions and during chronic cardiac overload. We hypothesize that acute activation of nSMase plays an important role in mechanical regulation of the heart, while chronically elevated membrane stretch results in constitutively increased nSMase activity which suppresses cardiac function, leads to structural remodeling and promotes cardiac arrhythmias. We further hypothesize that pathological nSMase signaling, including an increasing ceramide production and accumulation in damaged myocardium, may serve as an early ACM disease marker to detect preclinical ACM for genetically predisposed persons and identify people for whom early disease- modifying treatments may be appropriate. The research has high potential because the mechanistic insights gained from it can serve as a foundation for recognition of potential biomarkers of myocardial damage and identifying novel therapeutic targets aimed at prevention of cardiac remodeling during chronic overload.