Extensive Downregulation of Matrix Scaffolding Genes and TGF‐beta in Isolated Mitral Regurgitation in the Dog

The volume overload of isolated mitral regurgitation (MR) in the dog is characterized by LV dilatation and loss of extracellular matrix. We hypothesize that the MR heart is not only marked by increased matrix metalloproteinase (MMP) expression but also by downregulation of collagen synthesis. Gene arrays were compared from biopsy specimens obtained in 4 dogs prior to MR and 4 months after MR induction. There was a 50% increase in LV end‐diastolic volume by magnetic resonance imaging. MMP‐1 and ‐9 increased 5‐ and 10‐fold, in the face of no change in collagen I, a 1.5‐fold increase in collagen III, but a 35% decrease in LV hydroxyproline levels. Genes associated with cell‐matrix scaffolding including decorin, fibulin, fibrillin, were significantly downregulated. Genes regulating collagen synthesis including thrombospondin, TGF‐beta binding protein, TGF‐beta receptor, connective tissue growth factor, and plasminogen activator inhibitor were also significantly downregulated. LV TGF‐beta activity decreased 30% in MR compared to normal LV. These results indicate that LV collagen loss in MR is chiefly due to post‐translational processing and degradation of collagen I and III. In addition, there is an extensive downregulation of cell‐matrix scaffolding genes controlled by TGF‐beta pathway which is also downregulated. Taken together, this could explain why RAS blockade does not improve LV remodeling in isolated MR.