Long-term dietary allyl isothiocyanate, a TRPA1 agonist, ameliorates cardiac fibrosis and diastolic dysfunction in aged mice

Abstract

Transient receptor potential ankyrin 1 (TRPA1) is a sensory channel expressed in vagal afferent nerves that detect noxious stimuli. Trpa1 knockout accelerates age-related cardiac fibrosis and dysfunction in mice. This study investigated whether TRPA1 activation with its selective agonist, allyl isothiocyanate (AITC), prevents cardiac aging. Male and female 18-month-old C57BL/6 J mice were randomized to receive either a control diet or a diet containing 15 mg of AITC per kilogram of food for 6 months. At 24 months, aged mice on the control diet exhibited increased left ventricular wall thickness but maintained similar left ventricular volume and preserved systolic function compared to 18-month-old middle-aged mice. Additionally, aged mice on a control diet developed restrictive-like cardiomyopathy, characterized by a pathologically elevated E/A ratio. AITC treatment significantly improved diastolic function by normalizing the E/A ratio (P < 0.01) and shortening isovolumetric relaxation time (P < 0.01), without affecting left ventricular wall thickness, volume, or systolic function. Electrocardiographic analysis demonstrated that AITC treatment significantly increased heart rate variability (P < 0.01) and parasympathetic nervous system index (P < 0.05), indicating enhanced vagal activity. Histological analyses revealed decreased cardiac fibrosis and collagen I/III deposition in AITC-treated mice (all P < 0.01). Proteomics analysis demonstrated that differentially expressed proteins in myocardial tissue were mainly enriched in pathways of collagen metabolism, extracellular matrix-receptor interaction, and fatty acid metabolism. These findings suggest that long-term dietary AITC may improve vagal tone, reduce cardiac fibrosis, and enhance diastolic function in aged mice, potentially through TRPA1 activation. TRPA1 could be a promising therapeutic target for age-related diastolic dysfunction.

Keywords: Allyl isothiocyanate; Cardiac aging; Diastolic dysfunction; HFpEF; TRPA1.