Question : This project set out to characterize the effects of reduced endothelial cell cysteine catabolism (inducible endothelial cell-specific cystathionine gamma lyase (CSE) knockout mice/ CSE ^iEC mice) and to identify potential CSE- associated angiocrine effects on cardiomyocytes.

Methods and results : Analysis of CSE activity and H ₂ S levels (HPLC-MS/MS) in endothelial cells from 1, 3, 6 and 18 month old mice revealed a gradual decrease in H ₂ S production. This decrease was associated with the enhanced phosphorylation of CSE on Ser377, which inhibits its activity. To determine whether the deletion of endothelial cell CSE impacts on cardiac function, CSE ^iEC and wild type littermates were studied. Cardiac echocardiography and μCT analysis revealed an age dependent systolic and diastolic dysfunction, which was initiated at the 6 months and progressively enhanced in 18 month old CSE ^iEC mice - based on left ventricle posterior wall thickness. In addition, pulsed-wave Doppler recording showed severe right ventricular dysfunction, with significantly shorter pulmonary acceleration time and tricuspid annular plane systolic excursion measures. Histopathological characterization of hearts confirmed severe hypertrophy without signs of inflammation in hearts from CSE ^iEC mice compared to their wild type littermates. Interestingly, supplementation of sodium polysulthionate in the diet starting at 6 months of age prevented the progression of hypertrophy. Mechanistically, endothelial CSE deletion impacted on the cardiomyocyte transcriptional program and in particular induced NFAT mediated hypertrophic transcripts. Addition of hydrogen sulfide was able to inhibit NFAT activity and maintain cardiomyocyte fitness.

Conclusions : Age-related alterations in the endothelial cysteine catabolism impact on cardiac function through NFAT mediated control of the cardiomyocyte transcriptional program. Polysulfide supplementation might serve as a novel therapeutic strategy to inhibit NFAT and normalize cardiac function.