Abstract P2003: Loss of Trpa1 in Mice Leads to Age-Related Dilated Cardiomyopathy

Abstract

Activation of the transient receptor potential ankyrin 1 (TRPA1) channel, a mechanical and oxidative stress sensor, has been shown to slow down aging process and promote longevity in invertebrate animal models like Caenorhabditis elegans . Although physiologic sensory functions of TRPA1 are conservative across species, the role of TRPA1 in regulation of organ development and function in mammals in the aging process is unknown. The present study tests the hypothesis that TRPA1 ablation leads to cardiac dilation and cardiomyopathy in aging mice. Echocardiography was performed in male 12-week-old (young) and 52-week-old (older) Trpa1 gene knockout ( Trpa1 -/- ) mice and wild-type (WT) littermates on a mixed C57BL/6 x 129 genetic background. Echocardiogram data showed that, compared to young WT littermates, young Trpa1 -/- mice had similar cardiac dimensions and left ventricular function, as demonstrated by left ventricular end-diastolic internal dimension (LVIDd, WT 4.29±0.62 vs. Trpa1 -/- 4.50±0.41 mm, P>0.05), left ventricular ejection fraction (LVEF, a parameter of systolic function, WT 66.73±9.50 vs. Trpa1 -/- 63.39±12.76 %, P>0.05), and E/A ratio (a parameter of diastolic function, WT 1.23±0.03 vs. Trpa1 -/- 1.39±0.14, P>0.05). In contrast, older Trpa1 -/- mice developed dilated cardiomyopathy with dilated left ventricle (LVIDd: WT 4.60±0.16 vs. Trpa1 -/- 5.00±0.37 mm, P<0.05) and impaired left ventricular systolic function (LVEF: WT 58.04±9.27 vs. Trpa1 -/- 41.79±7.19 %, P<0.05) when compared to older WT mice. In addition, older Trpa1 -/- mice had impaired left ventricular myocardial performance index (LV MPI, a parameter of ventricular systolic and diastolic function, WT 0.62±0.15 vs. Trpa1 -/- 0.89±0.18, P<0.05) albeit left ventricular diastolic function was not different between old Trpa1 -/- and WT mice (E/A ratio: WT 1.53±0.22 vs. Trpa1 -/- 1.99±0.92, P>0.05). These results show that genetic knockout of TRPA1 leads to age-related left ventricular dilation and systolic dysfunction. These findings suggest that TRPA1 activation protects against age-related dilated cardiomyopathy.