Transforming growth factor-beta 1 in heart development

Abstract

Defined biochemical stimuli regulating neonatal ventricular myocyte (cardiomyocyte) development have not been established. Since cardiomyocytes stop proliferating during the first 3–5 days of age in the rodent, locally generated ‘anti-proliferative’ and/or differentiation signals can be hypothesized. The transforming growth factor-beta (TGF-β) family of peptides are multifunctional regulators of proliferation and differentiation of many different cell types. We have determined in neonatal and maturing rat hearts that TGF- β 1 gene expression occurs in pups of both normotensive (Wistar Kyoto, WKY) and hypertrophy-prone rats (spontaneously hypertensive, SHR). TGF- β 1 transcript levels were readily apparent in total ventricular RNA from SHR pups within 1 day of age and elevated in 3–7 day old WKY and SHR hearts when cardiomyocyte proliferation indices are diminished. TGF- β 1 transcript levels remain at a ‘relatively’ high level throughout maturation and into adulthood in both strains. Further, TGF- β 1 transcripts were localized to cardiomyocytes of neonatal rat ventricular tissue sections by in situ hybridization. Immunoreactive TGF-β was co-localized to the intracellular compartment of neonatal cardiomyocytes at the light and electron microscopic level. In vitro analysis using primary cultures of fetal and neonatal cardiomyocytes indicated that TGF-βs inhibit mitogen stimulated DNA synthesis and thymidine incorporation. From these data, we propose that locally generated TGF-βs may act as autocrine and/or paracrine regulators of cardiomyocyte proliferation and differentiation as intrinsic components of a multifaceted biochemical regulatory process governing heart development.