Abstract Body: Background: Aging promotes cardiac remodeling, dysfunction, fibrosis, and a chronic systemic inflammatory response. Increased NLRP3 inflammasome activity is associated with cardiovascular diseases and aging. Hydrogen sulfide (H₂S) has been shown to inhibit NLRP3 inflammasome formation and activation in the heart post-myocardial infarction and in primary cardiomyocytes subjected to simulated ischemia-reoxygenation.
Hypothesis: H₂S supplementation mitigates the development of age-associated cardiomyopathy, myocardial fibrosis and inflammasome activation.
Methods: Left ventricular (LV) systolic and diastolic function (isovolumetric relaxation time; IRT) were measured by echocardiography at 3 (young), 12 (middle-aged), and 24 (old) months in C57BL/6J mice. Two groups of mice were fed with a standard diet (SD) or SD enriched with SG1002 (H₂S donor, 40 mg/kg/day) starting at 12 months of age, for an additional 12 months. Interstitial fibrosis was detected with picrosirius red staining. Cardiac inflammasome activity was measured by immunofluorescence as aggregation of the inflammasome scaffolding protein, apoptosis speck-like protein (ASC), and with a cell-based interleukin-1 (IL-1) activity reporter assay to measure plasma IL-1 activity.
Results: Aging is associated with LV diastolic dysfunction, fibrosis and NLRP3 inflammasome activation. Treatment with SG-1002 prevented the development of diastolic dysfunction (Fig. A) at 24 months without affecting systolic function (Fig. B). SG-1002 treatment attenuated the increase in interstitial fibrosis observed at 24 months (Fig. C) and blunted the age-dependent increase in inflammasome with a reduction in ASC staining (Fig. D) and plasma IL-1 levels (Fig. E).
Conclusions: H₂S donor initiated in middle-aged mice preserves diastolic function in aging mice and reduces age-dependent increase in interstitial fibrosis and inflammasome activation, slowing down the cardiovascular aging process.