Abstract 4143988: Activation of TRPA1 with allyl isothiocyanate prevents age-related cardiac diastolic dysfunction

While its role in aging processes in mammals is largely unknown, activation of transient receptor potential ankyrin 1 (TRPA1), a sensor for noxious cold and oxidative stress , has been shown to decelerate aging and promote longevity in invertebrate animal models. Our previous study demonstrated that knockout of the Trpa1 gene accelerated age-related cardiac fibrosis and dysfunction in mice. The present study aimed to investigate whether activation of TRPA1 with its selective agonist allyl isothiocyanate (AITC) prevents age-related cardiac remodeling and dysfunction. Male and female 78-week-old aging C57BL/6J mice were randomized to receive either control diet or diet containing AITC (15 mg/Kg) for 26 weeks, and 12-week-old C57BL/6J mice were used as young controls. Transthoracic echocardiography was performed at the end of the experiment and showed that 104-week-old male and female aged mice that received control diet for 26 weeks developed restrictive-like diastolic dysfunction with significantly increased E/A ratio (2.41±0.84 vs. 1.22±0.03, P <0.01) and isovolumetric relaxation time (IVRT, 15.17±1.31ms vs. 10.32±1.81ms, P <0.01) compared to 12-week-old young mice. Remarkably, aged mice on AITC diet showed significantly improved diastolic function with decreased E/A ratio (1.60±0.24 vs. 2.41±0.84, P <0.01) and IVRT (11.75±2.09ms vs. 15.17±1.31ms, P <0.05) compared to aged mice on control diet. In contrast, the left ventricular end-diastolic and end-systolic wall thickness, internal diameter, and volume as well as left ventricular ejection fraction (young mice: 66.30±4.47% vs. aged mice on control diet: 59.49±11.27% vs. aged mice on AITC diet: 65.19±8.32%, P >0.05) were not significantly different among the three groups. Pathologic analyses demonstrated that aged mice on control diet developed increased cardiac collagen I, collagen III, and transthyretin deposition compared to young mice, which were significantly improved in aged mice on AITC diet. Taken together, these results show that aged mice developed restrictive-like cardiomyopathy with remarkable diastolic but not systolic dysfunction, and that chronic activation of TRPA1 with oral AITC prevented age-related cardiac fibrosis, transthyretin deposition, and diastolic dysfunction. These results indicate that TRPA1 may serve as a therapeutic target for age-related heart failure with preserved ejection fraction.