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MAST CELL BLOCKADE ATTENUATES THE COLLAGEN LOSS AND VENTRICULAR DILATION ASSOCIATED WITH MITRAL REGURGITATION IN DOGS
Author(s) -
Zheng Junying,
Dillon A. Ray,
Rynders Pat,
Tillson Michael,
Beard Debra,
Redmon Jim,
Dell’Italia Louis
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1262
Subject(s) - medicine , ventricle , chymase , cardiology , mast cell , extracellular matrix , blockade , mitral regurgitation , endocrinology , connective tissue , pathology , chemistry , receptor , immunology , biochemistry
In a canine model of mitral regurgitation (MR) induced by chordal rupture, we have shown infiltration of LV by mast cells and increased matrix metalloproteinase (MMP) activity, resulting in extracellular matrix (ECM) loss, myocyte and myofiber slippage, LV dilatation and failure. Mast cells release mediators that can affect LV ECM. We hypothesized that mast cell blockade with ketotofen (K, n=6) would result in improved LV remodeling compared to untreated dogs with four weeks of MR (n=6). Mean pulmonary artery pressures (13¡À1 vs. 20¡À3 mmHg, p<0.05) and SVR (1684¡À132 vs. 2151¡À147, p<0.05) were significantly decreased in K‐MR vs. MR dogs. K‐MR dogs had significantly smaller LV end‐diastolic dimensions, left atrium/aortic root ratio, and wall thinning (LVfw) vs. untreated MR dogs. K‐MR dogs had significantly less LV hypertrophy vs. MR dogs. LV collagen volume % was significantly higher in K‐MR dogs vs. MR dogs (0.50¡À0.033 vs. 0.34¡À0.017, p<0.05). The relative transcript abundance of collagen I ¦Á1 and fibronectin were significantly decreased in MR dogs compared to normal dogs (n=6) while in K‐MR these levels did not differ from normal (n=6) (p<0.05). K‐ MR dogs also had higher collagen III transcript levels vs. MR dogs. Thus, Ketotofen treatment restored synthesis of collagen matrix components and improved LV function and remodeling in MR. This may provide a new form of therapy for pure MR since renin‐angiotensin system blockade, which is anti‐fibrotic, does not improve LV remodeling and function in the pure volume overload of MR.