Mutation in collagen gene induces cardiomyopathy in transgenic mice.
In many remodeling tissues, such as the heart, collagen degradation to provide new integrin-binding sites is required for survival. However, complete loss of integrin signaling due to disconnection from extracellular matrix (ECM) leads to apoptosis and dilatation. To test the hypothesis that a mutation in type I collagen gene induces cardiomyopathy, we employed a metalloproteinase-resistant collagen mutant homozygous transgenic male (B6,129-Colla-1) and compared with age-sex matched wildtype C57BL/J6 control mice. At the age of 38-42 weeks, aortic and left ventricle (LV) pressure were measured. The LV wall thickness and diameter were measured by a digital micrometer. The levels of matrix metalloproteinase-2 (MMP-2) activity and cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4) were measured by zymography and Western blot analyses, respectively. The levels of collagenolysis were measured by Western blot using anti-collagen antibody. In transgenic and wildtype mice, end-diastolic pressure (EDP) was 8.3 +/- 1.7 and 6.5 +/- 1.1 mmHg; LV diameter was 3.43 +/- 0.07 and 2.94 +/- 0.05 mm; wall thickness was 1.18 +/- 0.03 and 1.28 +/- 0.04 mm; end-diastolic wall stress was 600 +/- 158 and 347 +/- 49 dynes/cm(2), respectively. The increase in LV wall stress was associated with increased MMP-2 activity, increased collagenolysis, and decreased levels of TIMP-4. This leads to reduced elastic compliance in collagen mutant transgenic mice. The occurrence of cardiomyopathy in adult Colla-1 mice may be a significant confounding factor as it may be indicative of increased basal levels of ECM disruption. This phenotype is what would be expected if collagen degradation normally supplies integrin ligands during cardiac muscle remodeling.
Miller
Amanda D
AD
Department of Physiology and Biophysics, School of Medicine, The University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Tyagi
Suresh C
SC
D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003094:Collagen / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D006335:Heart Injuries; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009638:Norepinephrine / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016277:Ventricular Function, Left
D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D004549:Elastin; D020778:Matrix Metalloproteinase 2; D009638:Norepinephrine