Significance of Fibrillin-1, Filamin A, MMP2 and SOX9 in Mitral Valve Pathology

Abstract

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ-relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1-2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets.

Keywords: Fibrillin 1 (FBN1); Filamin A (FLNA); SRY-box transcription factor 9 (SOX9); matrix metalloproteinase 2 (MMP2); mitral valve.

Figure 1

Venn diagram: (A). FBN1 vs. FNLA—from tissue samples, (B). FBN1 blood vs. FNLA blood, (C). FBN1 blood vs. SOX9 blood. Color code: yellow: mRNA expression 0, blue: mRNA expression 1, red: mRNA expression 2. Fisher’s exact test: Key: frequency/expected frequency.