Testosterone and interleukin-1β increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n
Open accessAbstract
Myocarditis and dilated cardiomyopathy (DCM) are often caused by viral infections and occur more frequently in men than in 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 = 4.2 × 10(-5)) and cardiac dilation (P = 0.008) were worse in males, there was no difference in viral replication in the heart. Fibrotic remodeling genes, such as tissue inhibitor of metalloproteinase (TIMP)-1 and serpin A 3n, were upregulated in males during myocarditis rather than during DCM. Using gonadectomy and testosterone replacement, we showed that testosterone increased cardiac TIMP-1 (P = 0.04), serpin A 3n (P = 0.007), and matrix metalloproteinase (MMP)-8 (P = 0.04) during myocarditis. Testosterone increased 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 (33%) genes identified in acute DCM patients were significantly altered in the heart during CVB3 myocarditis in mice, including serpin A 3n (3.3-fold change, P = 0.0001). Recombinant serpin A 3n treatment induced cardiac fibrosis during CVB3 myocarditis (P = 0.0008) while decreasing MMP-3 (P = 0.04) and MMP-9 (P = 0.03) levels in the heart. Thus, serpin A 3n was identified as a gene associated with fibr…
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Mast cells work in cooperation with macrophages to increase profibrotic inflammation and remodeling that leads to scar and DCM.
“Mast cells work in cooperation with macrophages to increase profibrotic inflammation and remodeling that leads to scar and DCM (Figure 4). 129,157,158,160”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
Testosterone increases TLR4, caspase-1, and IL-1β levels during CVB3 myocarditis in male mice, which have higher levels of cardiac inflammation.
“Additionally, testosterone increases TLR4, caspase-1, and IL-1 β levels during CVB3 myocarditis in male mice, which have higher levels of cardiac inflammation. 129”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
cMRI cannot identify specific cellular components of inflammation and may be less accurate in early stages of myocarditis because fibrosis typically develops weeks after acute myocarditis.
“cMRI cannot identify specific cellular components of inflammation and may be less accurate in the early stages of myocarditis because fibrosis typically develops weeks after acute myocarditis. 128-130”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
IL-1β levels in the heart correlate to the severity of inflammation in male BALB/c mice with autoimmune CVB3 myocarditis.
“IL-1 β levels in the heart correlate to the severity of inflammation in male BALB/c mice with autoimmune CVB3 myocarditis. 115,129”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
Mast cells are critical for the remodeling and fibrosis that lead to DCM, due to their release of profibrotic cytokines (eg, IL-1β, TGFβ1, and TNFα) and enzymes including Serpin A3n that are required to activate IL-1β and matrix metalloproteinases required for fibrosis.
“Mast cells are critical for the remodeling and fibrosis that lead to DCM, due to their release of profibrotic cytokines (eg, IL-1 β , TGF β 1 [transforming growth factor beta 1], and TNF α ), and many enzymes, including Serpin A3n ( α 1-antichymotrypsin), that are required to activate IL-1 β and matrix metalloproteinases that are required for fibrosis (Figure 4). 129,171”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
Mast cells and macrophages work together to drive inflammation and fibrosis.
“Mast cells and macrophages work together to drive inflammation and fibrosis. 129,158”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [129]
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Self-citation
- Authors
- Coronado, M. J., Brandt, J. E., Kim, E., Bucek, A., Bedja, D., Abston, E. D., Shin, J., Gabrielson, K. L., Mitzner, W., & Fairweather, D.
- Affiliations
- Department of Environmental Health Sciences, Bloomberg School of Public Health, and
- Johns Hopkins University (US)
- Corresponding author
- Fairweather, DeLisa
- ORCID
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2012-04-15
- Volume
- 302
- Issue
- 8
- Pages
- H1726-H1736
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC3330806
- OpenAlex
- W1994261011
- Cited by
- 116
- References
- 3
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 14 · 2023: 19 · 2022: 16 · 2021: 10 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 11 · 2013: 6 · 2012: 6
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL087033)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- dilated cardiomyopathy, cardiac remodeling, testosterone, IL-1β, sex differences, myocardial fibrosis, TIMP-1, matrix metalloproteinase-8, MMP-3, MMP-9, gonadectomy, viral myocarditis, gene expression
- MeSH terms
- Acute-Phase Proteins, Animals, Autoimmune Diseases, Coxsackievirus Infections, Female, Fibrosis, Male, Mice, Inbred BALB C, Molecular Sequence Data, Myocarditis, Myocardium, Orchiectomy, Ovariectomy, Viral Plaque Assay, Recombinant Proteins, Sex Characteristics, Testosterone, Serpins, Cytokines, Disease Progression, Ventricular Remodeling, Microarray Analysis, Mice, Interleukin-1beta, Real-Time Polymerase Chain Reaction
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