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A secretion trap screen in yeast identifies protease inhibitor 16 as a novel antihypertrophic protein secreted from
Robert J A Frost1, Stefan Engelhardt
1Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Wuerzburg, Versbacher Strasse 9, 97078 Wuerzburg, Germany.
Circulation
|October 3, 2007
Summary
Protease inhibitor 16 (PI16), a novel secreted cardiac protein, is upregulated in heart failure and inhibits cardiomyocyte growth. This discovery suggests PI16 as a potential therapeutic target for heart failure treatment.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Heart Failure Pathophysiology
Background:
- Cardiomyocyte hypertrophy is a key factor in congestive heart failure development.
- The role of endogenous secreted cardiac proteins in myocardial hypertrophy remains largely unexplored.
Purpose of the Study:
- To identify cardiac proteins secreted from the myocardium.
- To investigate the function of these secreted proteins in cardiomyocyte growth and heart failure.
Main Methods:
- Genetic yeast secretion trap screen with a murine cardiac cDNA library.
- mRNA and protein expression analysis in failing hearts and primary cardiomyocytes.
- In vitro studies on PI16 secretion and its effect on cardiomyocyte growth.
- In vivo studies using transgenic mice with cardiomyocyte-specific PI16 overexpression.
Main Results:
- Identified 54 cardiac proteins with secretion signals.
- Protease inhibitor 16 (PI16) mRNA and protein levels were significantly upregulated in hypertrophic and failing myocardium.
- PI16 is secreted by cardiomyocytes and inhibits their growth in vitro.
- Suppression of PI16 enhanced cardiomyocyte size, while PI16 overexpression in transgenic mice resulted in smaller hearts with hypotrophic cardiomyocytes.
Conclusions:
- PI16 is a novel protein secreted by the heart that is upregulated early in heart failure.
- PI16 inhibits cardiomyocyte growth both in vitro and in vivo.
- PI16 represents a potential novel therapeutic target for managing heart failure.
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