Introduction:
Acute rheumatic fever (ARF) results from autoimmune responses to group A streptococcus. ARF can cause chronic rheumatic heart valve disease (RHVD), a major public health burden in low- and middle-income countries. Although ARF affects both sexes equally, females have a higher prevalence of RHVD. We identified a target protein, ProTα, that may contribute to pathophysiology of and gender predisposition in RHVD. Estradiol regulates ProTα, which influences transcriptional activity of the estrogen receptor (ER).
Methods:
Human heart valves (n=120) obtained from heart transplantation and valve replacement surgeries, including non-diseased mitral and aortic valves (NDMV and NDAV, n=17/group), rheumatic mitral and aortic valves (RMVD, n=45; RAVD, n=8) and calcifying valves from patients with calcific aortic valve disease (CAVD, n=33) underwent proteomic and network analyses, and immunohistochemical assessment of CD68, CD4, CD8 and ProTα. ProTα levels were measured in plasma and peripheral mononuclear cells (PBMCs) from RHVD patients and healthy donors (n=14/group) by ELISA and flow cytometry.
Results:
A comparison of proteomes from NDMV and NDAV established the baseline differences between valve types. 12 proteins were enriched (q<0.05) in NDMV that may indicate the mitral valve predisposition to RVHD. Proteome analysis of non-diseased and diseased valves (NDMV vs RMVD, NDAV vs RAVD) identified a total of 213 proteins enriched in RHVD (q<0.05). The expression of the 12 NDMV-enriched proteins were evaluated across the 213 proteins enriched in diseased valves, resulting in the identification of ProTα common to both the RMVD and RAVD proteomes, but absent in CAVD. Additional KEGG pathway enrichment analyses linked 6 among 213 proteins with the estrogen signaling pathway (p<0.05). Immunoreactive ProTα colocalized with T CD8 cells in RHVD. ProTα and ERα also correlated strongly in circulating T CD8 cells in RHVD (p<0.05). ProTα plasma levels were higher in RHVD patients than healthy individuals (2 fold, p<0.05).
Conclusion:
We propose that ProTα is a novel contributor to the immunopathogenesis of RHVD and may regulate sex predisposition in this disease.