Background and Aims

Duchenne Muscular Dystrophy (DMD) is often associated with dilated cardiomyopathy. The underlying mechanisms initiate the cardiovascular dysfunctions are unknown. Recent studies demonstrated the pathophysiological role of Tenascin-C (TNC) in heart failure and vascular disease.

We aimed to 1) assess the progression of cardiac and vascular dysfunction and 2) to explore the role of TNC and oxidative stress in cardiovascular abnormalities in a mouse model of DMD.

Methods

Male mdx and BL/10 mice were used to assess the cardiac function by echocardiography and hemodynamic measurements. Vascular function was assessed on isolated aortic rings by wire myography and the rings were treated by NAPH oxidase inhibitor (Apocynin). Cardiac fibrosis and TNC expression in LV tissue were assessed. HUVECs were treated either with TNC or combination with TLR-4 inhibitor (TAK-242) and inflammatory and oxidative stress markers were analysed by RT-qPCR.

Results

LV dilation, reduction in LV systolic pressure and fibrosis were enhanced in mdx mice compared to controls. Similarly, TNC protein expression was increased both plasma and LV tissue in mdx mice. Vascular endothelial function was impaired in mdx mice. HUVECs incubated with TNC showed increased expression of IL-6 and oxidative stress markers. TLR-4 inhibitor or NADPH oxidase inhibitor significantly reversed inflammatory response in HUVEC and improved endothelial dysfunction, respectively.

Conclusions

To conclude, the progression of cardiovascular dysfunction are accompanied by TNC upregulation in mdx mice. Cardiac fibrosis and vascular endothelial function in DMD may drive by TNC via TLR-4 activation, suggesting that TNC represents a novel player in the progression cardiovascular abnormalities in DMD.