J Korean Med Sci.  2008 Feb;23(1):41-48. 10.3346/jkms.2008.23.1.41.

Overexpression of Transforming Growth Factor-beta1 in the Valvular Fibrosis of Chronic Rheumatic Heart Disease

• Kim L
• Kim DK
• Yang WI
• Shin DH
• Jung IM
• Park HK
• Chang BC

• KMID: 1786843
• DOI: http://doi.org/10.3346/jkms.2008.23.1.41

Abstract

For the purpose of determining the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the mechanism of chronic rheumatic heart disease, we evaluated the expression of TGF-beta1, proliferation of myofibroblasts, and changes in extracellular matrix components including collagen and proteoglycan in 30 rheumatic mitral valves and in 15 control valves. High TGF-beta1 expression was identified in 21 cases (70%) of rheumatic mitral valves, whereas only 3 cases (20%) of the control group showed high TGF-beta1 expression (p<0.001). Additionally, increased proliferation of myofibroblasts was observed in the rheumatic valves. High TGF-beta1 expression positively correlated with the proliferation of myofibroblasts (p=0.004), valvular fibrosis (p< 0.001), inflammatory cell infiltration (p=0.004), neovascularization (p=0.007), and calcification (p<0.001) in the valvular leaflets. The ratio of proteoglycan to collagen deposition inversely correlated with TGF-beta1 expression in mitral valves (p=0.040). In conclusion, an ongoing inflammatory process, the expression of TGF-beta1, and proliferation of myofibroblasts within the valves have a potential role in the valvular fibrosis, calcification, and changes in the extracellular matrix that lead to the scarring sequelae of rheumatic heart disease.

Keyword

Rheumatic Heart Disease; Transforming Growth Factor-beta1; Heart Valves; Fibrosis

MeSH Terms

Adult
Aged
Chronic Disease
Collagen/metabolism
Female
Fibrosis
Humans
Immunohistochemistry
Male
Middle Aged
Mitral Valve/*pathology
Proteoglycans/metabolism
Rheumatic Heart Disease/*metabolism/pathology
Transforming Growth Factor beta1/analysis/*physiology

Figure

• 

  Fig. 1 Histologic and immunohistochemical findings of control valves. (A) Valvular leaflets obtained from the control group showed well-preserved leaflet architecture without fibrosis or inflammatory cell infiltration (H&E, ×40). (B) Immunohistochemical staining for TGF-β1 demonstrated positivity in the subendothelial stroma of valvular leaflets (TGF-β1, ×40).

• 

  Fig. 2 Histologic and immunohistochemical findings of the rheumatic mitral valves. (A) Rheumatic mitral valves showed severe fibrosis and distorted architecture (H&E, ×40). (B) A high-power view demonstrated small thin-walled vessels and perivascular lymphocytic infiltration (H&E, ×200). (C) High TGF-β1 expression was seen in the endothelial cells and smooth muscle cells of the vessels, in the perivascular interstitial cells, and stroma of the valves (×200). (D) Myofibroblasts that were positive for SMA immunostaining were present in the subendothelial densely fibrotic area (×40).

• 

  Fig. 3 Proteoglycan and collagen deposition in rheumatic mitral valves and control valves. (A) The proportion of proteoglycan deposited areas was lower in rheumatic mitral valve group (RM) than in the control group (black bars represented mean values: 3.75% vs. 13.2%) (p=0.014). (B) The rheumatic mitral valve group (RM) showed extensive collagen deposition compared to the control group (black bars represented mean values: 23% vs. 11.2%) (p<0.001). (C) The ratio of proteoglycan to collagen deposited areas was lower in the TGF-β1 positive group than in the TGF-β1 negative group (black bars represented mean values: 0.38 vs. 0.66) (p=0.040).

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