DECREASED COLLAGEN MESSENGER-RNA AND REGRESSION OF CARDIAC FIBROSIS IN THE VENTRICULAR MYOCARDIUM OF THE TIGHT SKIN MOUSE FOLLOWING THYROID-HORMONE TREATMENT

Objective: The aim was to study the effect of thyroid hormone on collagen gene expression in the myocardium of the tight skin mouse (TSK), a genetic model of myocardial fibrosis. Methods: Heterozygous male (TSK/+) (n=20) and normal (+/+) homozygous mice (n=20), 1.5-2 months old of the C57 BL/6 strain were studied. Ventricular hypertrophy following thyroid hormone treatment (L-thyroxine, 10-mu-g.100 g-1 body weight daily intraperitoneally) was examined by measurement of the heart weight/body weight ratios and histological changes. Expression of fibrillar collagen types I and III in the ventricular myocardium was examined by measurement of the abundance of their respective mRNAs. Collagen synthesis was examined by measurement of hydroxyproline. Deposition of collagen types was evaluated by immunofluorescence staining. Expression of noncollagenous proteins, sarcomeric and cytoskeletal actin, was measured at the mRNA level. Results: After 12 days of treatment ventricular hypertrophy was induced in the heart of the TSK mice. The results of northern hybridisation analyses showed that in the hearts of TSK mice 24 h after thyroxine treatment the abundance of mRNA for pro alpha-2 (I) collagen was decreased by 32% (p<0.05), pro alpha-1 (III) collagen by 47% (p<0.002), cytoskeletal actin by 50% (p<0.005), and sarcomeric actin mRNA by 34% (p<0.01) compared to the untreated TSK mice. The abundance of mRNA for pro alpha-2 (I) and pro alpha-1 (III) collagens in the thyroxine treated TSK mice were nearly comparable to that in normal homozygous mice. In TSK mice which were treated for 12 d, collagen content of the ventricular myocardium, as determined by hydroxyproline measurements, was decreased by 22.5% (p<0.01) compared to that in the heart of normal homozygous mice. Conclusions: Effects of thyroid hormone on ventricular gene expression in TSK mice result in a diminished collagen mRNA and collagen content and the disappearance of cardiac fibrosis. Thyroid hormone may selectively prevent the induction of cardiac fibrosis and play an important role in regression of cardiac fibrosis via endocrine pathways.