Differential induction of cellular proliferation, hypertrophy and apoptosis in H9c2 cardiomyocytes by exogenous tissue factor
- 205 Downloads
Recent evidence has shown that prolonged exposure to exogenous tissue factor (TF) can alter the cellular functions of cardiomyocytes resulting in cardiac dysfunction. The effect of TF may arise from local inflammation within or in the vicinity of the heart. The aim of this study was to investigate the effect of TF on cardiomyocyte proliferation and growth. H9c2 rat cardiomyocytes were exposed to a range of concentrations of recombinant TF (rTF) (1.3–52 ng/ml) for up to 10 days and the outcome on cell proliferation and induction of apoptosis measured. At lower concentrations examined (1.3 ng/ml), rTF had a proliferative influence on the H9c2 cells. In contrast, elevated concentrations of rTF (52 ng/ml) induced cellular apoptosis as indicated by increased caspase-3 activity and nuclear localisation of p53. Moreover, incubation with intermediate concentrations of rTF (13 ng/ml) resulted in an initial increase in proliferation but subsequently, led to cellular apoptosis by day 7 of the incubation. In order to determine if these effects induced hypertrophic cell growth, expression of mechano-growth factor (MGF) was analysed. Incubation of cells with rTF resulted in enhanced expression of MGF particularly at the intermediate concentrations of rTF (13 ng/ml) as well as mean cellular transverse diameter. In addition, there was a rapid increase in the expression of atrial natriuretic factor (ANF) in the cells, on incubation with rTF but diminished rapidly when exposed to higher concentrations of rTF. These data indicate that exposure to increasing concentrations of rTF can accelerate the rate of cardiomyocyte turnover which may ultimately lead to depletion of viable cells within the heart. Moreover, at lower concentrations of rTF, the induction of cell proliferation together with hypertrophic markers indicates that rTF may contribute to the induction and progression of cardiac hypertrophy.
KeywordsTissue factor H9c2 cardiomyocytes Proliferation Apoptosis MGF Hypertrophy
We acknowledge the support of Heart Research UK for this work.
- 9.Pawlinski R, Fernandes A, Kehrle B, Pedersen B, Parry G, Erlich J, Pyo R, Gutstein D, Zhang J, Castellino F, Melis E, Carmeliet P, Baretton G, Luther T, Taubman M, Rosen E, Mackman N (2002) Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proc Natl Acad Sci USA 99:15333–15338CrossRefPubMedGoogle Scholar
- 16.Muller DN, Mervaala EM, Dechend R, Fiebeler A, Park JK, Schmidt F, Theuer J, Breu V, Mackman N, Luther T, Scheider W, Gulba D, Ganten D, Haller H, Luft FC (2000) Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am J Pathol 157:111–122PubMedGoogle Scholar
- 20.Hutter R, Valdiviezo C, Sauter BV, Savontaus M, Chereshnev I, Carrick FE, Bauriedel G, Luderitz B, Fallon JT, Fuster V, Badimon JJ (2004) Caspase-3 and tissue factor expression in lipid-rich plaque macrophages: evidence for apoptosis as link between inflammation and atherothrombosis. Circulation 109:2001–2008CrossRefPubMedGoogle Scholar
- 29.Mackman N (1995) Regulation of tissue factor gene. FASEB 9:883–889Google Scholar
- 32.Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, Kambayashi Y, Inouye K, Imura H (1991) Brain natriuretic peptide as a novel cardiac hormone in humans Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 87:1402–1412CrossRefPubMedGoogle Scholar