Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than women, but the reasons for the sex difference remain unclear. The aim of this study was to assess whether gene changes in the heart during coxsackievirus B3 (CVB3) myocarditis in male and female BALB/c mice predicted worse DCM in males. Although myocarditis (p = 4.2x10-5) and cardiac dilation (p = 0.008) were worse in males there was no difference in viral replication in the heart. Fibrotic remodeling genes like Timp-1 and Serpin A 3n were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement we show that testosterone increased cardiac Timp-1 (p = 0.04), Serpin A 3n (p = 0.007) and Mmp8 (p = 0.04) during myocarditis. Testosterone increased interleukin (IL)-1β levels in the heart (p = 0.02), a cytokine known to regulate cardiovascular remodeling, and IL-1β in turn increased cardiac Serpin A 3n mRNA (p = 0.005). We found that 39 of 118 or 33% of genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including Serpin A 3n (fold change 3.3, p = 0.0001). Recombinant Serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (p = 0.0008) while decreasing Mmp3 (p = 0.04) and Mmp9 (p = 0.03) levels in the heart. Thus, Serpin A 3n was identified as a gene associated with fibrotic cardiac remodeling and progression to DCM in male myocarditis patients and mice.
- dilated cardiomyopathy
- sex differences
- Copyright © 2011, American Journal of Physiology - Heart and Circulatory Physiology