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Controlled expression of cardiac-directed adenylylcyclase type VI provides increased contractile function
Mei Hua Gao1, Hamed Bayat, David M Roth
1Collateral Therapeutics Incorporated, San Diego, CA, USA.
Cardiovascular Research
|October 24, 2002
Summary
We created a new model of transgenic mice with inducible cardiac adenylyl cyclase type VI (AC(VI)) expression. This allows controlled study of AC(VI) effects on heart function without confounding transgene interactions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Transgenic Animal Models
Background:
- Constitutively active transgenes can complicate studies of cardiac function.
- Previous work showed adenylyl cyclase type VI (AC(VI)) improves heart function in mice.
- A need exists for inducible models to avoid transgene interactions.
Purpose of the Study:
- To develop a tetracycline-regulated transgenic mouse model for cardiac-specific AC(VI) expression.
- To investigate the kinetics of AC(VI) transgene expression and suppression.
- To assess the functional impact of inducible AC(VI) on cardiac function.
Main Methods:
- Generated transgenic mice with a tetracycline (tet)-controlled transactivator (tTA) under the alpha-myosin heavy chain promoter.
- AC(VI) expression was driven by a tet-response element (TRE) and a minimal CMV promoter.
- Assessed AC(VI) protein and mRNA levels, cAMP production, and left ventricular function.
Main Results:
- Successful suppression of cardiac AC(VI) protein during doxycycline treatment.
- 10-day removal of suppression led to a 10-fold increase in cardiac AC(VI) protein and mRNA.
- Inducible AC(VI) increased cAMP production and enhanced left ventricular contractile function.
Conclusions:
- Generated a novel transgenic mouse model with controlled cardiac AC(VI) expression.
- Determined AC(VI) protein half-life to be 2-3 days.
- Demonstrated that controlled cardiac transgene expression can improve cardiac myocyte cAMP generation and contractile function.