Mutation in collagen gene induces cardiomyopathy in transgenic mice*

Abstract

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.

Asiatic Acid Attenuates the Progression of Left Ventricular Hypertrophy and Heart Failure Induced by Pressure Overload by Inhibiting Myocardial Remodeling in Mice

“…21 Collagen type I is the most abundant collagen type in the heart, constituting approximately 50%-80% of the extracellular matrix (ECM). 4 Miller et al 22 reported that transgenic mice overexpressing the collagen I gene exhibited enhanced cardiac fibrosis and dysfunction. Consistent with previous studies, we noted marked fibrosis and increased a-SMA, and collagen I protein expression in the pressure-overloaded myocardium.…”

Developmental and Extracellular Matrix-Remodeling Processes in Rosiglitazone-Exposed Neonatal rat Cardiomyocytes

“…Increased basal levels of extracellular matrix degradation have been attributed to the development of cardiomyopathy in collagen I mutant mice [60]. Careful study of collagen I mutant mice revealed that turnover of extracellular matrix components is strongly interwoven and alterations in extracellular matrix composition may provoke cardiac dysfunction [58].…”

Gelatinase B(MMP-9) an apoptotic factor in diabetic transgenic mice

“…This drug had minimal effects on cardiovascular function in mice [26]. The aortic blood pressure, heart rate (HR), and systolic and diastolic blood pressure (SBP, DBP) were measured by a PE-10 catheter in aorta through the right common carotid artery [27]. After arterial pressure measurements, the catheter was advanced to LV and LVP, EDP and dP/dt were measured.…”