The Role Of TRPA1 In Cardiac Hypertrophy And Its Underlying Mechanism

Background:Pathological cardiac remodeling is a key pathophysiological process in heart failure?HF?,and cardiac hypertrophy is one of the main characteristics of pathological cardiac remodeling.Studies have shown that the main predictor of HF is the persistent cardiac hypertrophy,which is the independent risk factor for cardiovascular events such as malignant arrhythmia and sudden cardiac death as well.Transient receptor potential ankyrin 1?TRPA1?is a non-selective Ca²⁺channel with high permeability to Ca²⁺.Studies have suggested that TRPA1 is expressed in cardiovascular system and participates in the development and progression of many cardiovascular diseases,but its role in cardiac hypertrophy is still unclear.Objective:To explore the role of TRPA1 in cardiac hypertrophy induced by transverse aortic constriction?TAC?surgery.Methods:We explored the TRPA1 expression in DCM patients and hypertrophic mouse hearts.Male C57/B6 mice?weighing 23.5-27.5g?were selected to establish the pressure overload-induced cardiac hypertrophy model by transverse aortic constriction?TAC?technology.TRPA1 inhibitors HC-030031?HC?and TCS-5861528?TCS?were given daily for 4 weeks.Echocardiography and hemodynamic analysis were used to detect the change of cardiac function.The HW/BW,LW/BW,HW/TL and HW/TL ratios were weighed and calculated in the mice.We can evaluate the cardiomyocyte cross-sectional area by Hematoxylin and eosin?HE?and wheat germ agglutinin?WGA?staining,and the extent of fibrosis was assessed by Picrosirius red?PSR?staining.RT-PCR was used to perceive the mRNA expression level of ANP,BNP,?-MHC,CTGF,Collagen I and Collagen?.Western blotting was used to detect the expression of CaMKII and calcineurin.Histological analyses and flow cytometry were used to evaluate macrophage infiltration and M2 macrophages polarization.Results:?1?The results indicated that the TRPA1 expression level was observably upregulated in DCM patients and hypertrophic mouse hearts.?2?The animals exhibited significantly cardiac dilation and diastolic function after TAC surgery,and HC and TCS treatment improved cardiac dysfunction.?3?HW/BW,LW/BW,HW/TL,LW/TL ratios and CSA were significantly increased in TAC group.Similarly,the mRNA expression of ANP,BNP,and?-MHC were also significantly increased in TAC group.Interestingly,HC and TCS treatment markedly attenuated pathological cardiac hypertrophy.?4?Collagen volume and the mRNA levels of CTGF,collagen I and collagen III were markedly increased in the TAC-treated mice.HC and TCS treatment markedly attenuated pressure overload-induced cardiac fibrosis.?5?The results showed that the pressure overload significantly increased calcineurin activity and CaMKII expression,while HC and TCS treatment significantly attenuated calcineurin activity and CaMKII autophosphorylation.?6?The results showed that HC and TCS treatment attenuated macrophage infiltration and M2 macrophages polarization.Conclusions:TRPA1 inhibition protects against cardiac hypertrophy and fibrosis and these results suggest that TRPA1 may represent a potential therapeutic drug target for HF and cardiac hypertrophy.