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Role of S100A4 in cardiac hypertrophy and development

Mikael Schneider  


In this PhD thesis, I present evidence of two novel roles of S100A4 protein in   cardiac development and disease. The data was generated during my fellowship at   the Laboratory of Molecular and Cellular Cardiology, Copenhagen University   Hospital, during the period from July 2003 to December 2006.  

It has become apparent that the biological processes underlying cardiac hypertrophy   bear resemblance to the development of cancer. In support of this notion, our laboratory   previously identified the metastasis-associated protein S100A4 as part of the gene   program activated in cardiac hypertrophy. S100A4 is a member of the S100 family of   Ca2+-binding proteins and is well known for its implications in tumor metastasis and   tissue remodeling. S100A4 is multifunctional in that it functions both intracellularly,   interacting with the cytoskeleton and promoting cell motility, and extracellularly as a   paracrine factor eliciting cellular responses including growth and survival.

We now show that S100A4 levels are highly increased in hypertrophic hearts and   localizes to interstitial cells of the myocardium. Moreover, we for the first time   describe hypertrophic growth- and survival-promoting activity of S100A4 on cardiac   myocytes.  

Another widely accepted assumption is that the mechanisms underlying cardiac hypertrophy share common features driving cardiac development. We therefore also   sought for a role of S100A4 in cardiomyogenesis – the making of new cardiac   myocytes – using the in vitro model of cardiac differentiation termed embryoid bodies.   Indeed, we found a cardiomyogenic effect of S100A4 on early cardiac progenitors.  

Along with previously established angiogenic and cell motility-stimulating effects of S100A4, our findings suggest that S100A4 may protect the injured myocardium.   Intriguingly, the list of diseases involving S100A4 is continually growing, making   S100A4 a common denominator for pathological tissue remodeling and cell motility –   and perhaps a regenerative factor. The future will show whether S100A4 will become a   drug target or even a drug itself.