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Testosterone and interleukin-1β increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n

Michael J Coronado1, Jessica E Brandt, Eunyong Kim

  • 1Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|February 14, 2012
PubMed

Insights

Testosterone exacerbates viral myocarditis in males by upregulating fibrotic genes like serpin A 3n, contributing to dilated cardiomyopathy (DCM) progression. This sex difference in cardiac remodeling is linked to hormonal influences.

Area of Science:

  • Cardiovascular Research
  • Immunology
  • Genetics

Background:

  • Myocarditis and dilated cardiomyopathy (DCM) affect men more than women, but the underlying reasons are unclear.
  • Viral infections, such as coxsackievirus B3 (CVB3), are common causes of myocarditis and subsequent DCM.

Purpose of the Study:

  • To investigate sex-based differences in cardiac gene expression during CVB3-induced myocarditis.
  • To determine if testosterone influences cardiac remodeling and disease progression in male mice.

Main Methods:

  • Comparison of CVB3 myocarditis and cardiac dilation severity between male and female BALB/c mice.
  • Gene expression analysis of fibrotic remodeling and inflammatory markers.
  • Gonadectomy and testosterone replacement experiments.
  • In vivo assessment of serpin A 3n's role in cardiac fibrosis.

Main Results:

  • Male mice exhibited more severe myocarditis and cardiac dilation than females, despite similar viral replication.
  • Testosterone significantly upregulated cardiac TIMP-1, serpin A 3n, and MMP-8 in males.
  • Testosterone increased cardiac IL-1β, which in turn upregulated serpin A 3n.
  • Serpin A 3n was identified as a key gene altered during myocarditis, correlating with DCM in patients and mice.
  • Exogenous serpin A 3n induced cardiac fibrosis during myocarditis.

Conclusions:

  • Testosterone drives fibrotic gene expression, including serpin A 3n, in male hearts during viral myocarditis.
  • Serpin A 3n is a critical mediator of cardiac fibrosis and progression to DCM in males.
  • Hormonal factors contribute significantly to sex disparities in myocarditis and DCM outcomes.

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