Myocardial fibrosis in transforming growth factor beta(1) heterozygous mice

Aging is associated with an increase in myocardial extracellular matrix com ponents and contractile dysfunction. Transforming growth factor-beta(1) (TG F-beta(1)) has been shown to regulate expression of collagen genes and extr acellular matrix component synthesis in the heart, and may contribute to th e increase in myocardial fibrosis with aging. Therefore, we examined whethe r TGF-beta(1) heterozygous mutant mice-would exhibit less age-associated my ocardial fibrosis than normal mice. Twelve heterozygous TGF-beta (+/-) defi cient mice and 26 wild-type controls were examined to determine if there wa s a difference in development of myocardial fibrosis or mortality at 24 mon ths of age due to the loss of one TGF-beta(1) allele. Animals which survive d to 24 months of age were killed, and morphometric and functional studies were performed in isolated perfused hearts and in hearts from 6 month old c ontrol mice. Pressure-volume relations of the LV were assessed in the isovo lumic (balloon in LV) Langendorff preparation. Eleven of 12 (92%) TGF-beta( 1) deficient mice survived to 24 months of age in comparison to 66% (12/18) age-matched controls (P<0.05). Hearts from the 24 month old TGF-beta(1) de ficient mice exhibited a decrease in myocardial fibrosis (4+/-1 v. 10+/-1% average LV fibrosis in TGF-beta(1) (+/-) and age-matched controls, respecti vely (P<0.05) and greater compliance (i.e., lower LV end-diastolic pressure at a given balloon volume), decreased myocardial stiffness, and shorter co ntractile duration in comparison to 24-month-old wild-type controls. This s uggests that modulation of collagen production and/or degradation by TGF-be ta(1) may contribute to changes in myocardial structure and function with a ge. Thus, loss of one TGF-beta(1) allele appears to ameliorate age associat ed myocardial fibrosis and improve LV compliance, which may contribute to i ncreased survival over the life span of these mice. (C) 2000 Academic Press .