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Heat shock protein-56 is induced by cardiotrophin-1 and mediates its hypertrophic effect
J E Railson1, K Lawrence, J C Buddle
1Medical Molecular Biology Unit, The Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
Insights
Cardiotrophin-1 (CT-1) induces heat shock protein 56 (hsp56) in cardiac cells. Hsp56 overexpression significantly increases cardiac cell size, demonstrating its role in CT-1-induced cardiac hypertrophy.
Area of Science:
- Cardiovascular Biology
- Molecular Cell Biology
- Cytokine Signaling
Background:
- Cardiotrophin-1 (CT-1), an IL-6 family cytokine, exhibits protective and hypertrophic effects on the heart.
- CT-1 upregulates heat shock proteins (HSPs) like hsp70 and hsp90, implicated in cellular protection.
- The role of other HSPs, such as hsp56 (FKBP59), in CT-1's cardiac effects remains unclear.
Purpose of the Study:
- To investigate the induction and functional role of heat shock protein 56 (hsp56) in CT-1-mediated cardiac hypertrophy.
- To determine if hsp56 contributes to the hypertrophic response in primary neonatal rat cardiac myocytes.
Main Methods:
- CT-1 treatment was used to assess hsp56 mRNA and protein expression in cardiac cells.
- Overexpression of hsp56 was achieved using plasmid and Herpes viral vectors in neonatal rat cardiac myocytes.
- Antisense constructs were employed to inhibit hsp56 expression and evaluate its impact on CT-1's hypertrophic effect.
Main Results:
- CT-1 treatment significantly increased both mRNA and protein levels of hsp56.
- Overexpression of hsp56 led to a marked increase in cardiac myocyte size and protein:DNA ratio.
- Hsp56 knockdown using antisense constructs blocked the hypertrophic effect of CT-1, while hsp27, hsp70, and hsp90 overexpression did not affect cell size.
Conclusions:
- Heat shock protein 56 (hsp56) is induced by Cardiotrophin-1 (CT-1) in cardiac cells.
- Hsp56 plays a critical role in mediating CT-1-induced cardiac hypertrophy, distinct from the protective roles of hsp70 and hsp90.
- This study identifies hsp56 as the first heat shock protein demonstrated to have a hypertrophic effect in cardiac myocytes.
Abstract:
Cardiotrophin-1 (CT-1) is an interleukin-6 family cytokine with known protective and hypertrophic effects in the heart. Previous studies have shown that CT-1 treatment increases heat shock protein 70 (hsp70) and heat shock protein 90 (hsp90) levels in cardiac cells. Due to the known protective effects of hsp90 and hsp70, induction of these proteins may be involved in the protective effects of CT-1. We show here that heat shock protein 56 (hsp56), also known as FK506 binding protein 59 (FKBP59), is induced by CT-1 treatment at both the mRNA and protein levels. It has been demonstrated previously that, unlike hsp70 and hsp90, hsp56 overexpression does not protect cardiac myocytes against stressful stimuli. The other known effect of CT-1 is hypertrophy, an increase in cell size without cell division, which occurs in many cardiac pathologies. We investigated the role of hsp56 in the hypertrophic response of primary neonatal rat cardiac myocytes, using overexpression with transiently transfected plasmid vectors and Herpes viral vectors. Overexpression of hsp56 caused a significant increase in cardiac cell size and protein:DNA ratio. Hsp27, hsp70 and hsp90 overexpression had no effect on cell size. An antisense construct to hsp56 reduced hsp56 levels when transiently transfected and blocked the hypertrophic effect of CT-1. This is the first time that a hypertrophic effect has been demonstrated for a heat shock protein and demonstrates that CT-1-induced hypertrophy involves a specific hsp, which is not involved in its protective effect.