© 2007 European Society of Cardiology
Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding
a Center for Gender in Medicine (GiM), and Cardiovascular Research Center (CCR), Charité, Universitätsmedizin Berlin Germany
b Department of Cardiology, CVK, Charite, Universitätsmedizin Berlin Germany
c German Heart Center, DHZB, Berlin Germany
d Franz-Volhard-Clinic, HELIOS Clinics GmbH Charité CCB, Germany
e FibroGen Inc. San Francisco, CA, United States
f Department of Cardiology, West German Heart Centre, University Duisburg-Essen Essen, Germany
g St. Elisabeth Hospital Halle, Germany
* Corresponding author. Center for Gender in Medicine (GiM), and Cardiovascular Research Center (CCR), Charité, Universitätsmedizin Berlin, Germany, Hessische Street 3–4, 10115 Berlin, Germany. Tel.: +49 30 450 525 172; fax: +49 30 450 525 972. E-mail address: vera.regitz-zagrosek{at}charite.de
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Abstract |
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Background: Pressure overload leads to myocardial remodelling with collagen accumulation, left ventricular hypertrophy (LVH), neurohormonal activation and myocardial dysfunction. Prolyl 4-hydroxylases (P4H) are involved in collagen maturation. Inhibition of P4H has been shown to prevent LV remodelling and improve survival post-myocardial infarction.
Aim: To evaluate the role of P4H in pressure overload-induced myocardial remodelling.
Methods: Male Wistar rats underwent thoracic aortic banding (AoB) and were treated with a P4H inhibitor (P4HI) or vehicle (control). Echocardiography and haemodynamic measurements were performed after 4 weeks. Collagens, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMP), growth factors and neurohormonal markers were quantitated in LV samples.
Results: AoB led to LVH, increased LV enddiastolic pressure (LVEDP) and decreased contractility compared to sham. P4HI reversed these effects. AoB increased collagen I and III expression, which was normalized by P4HI. AoB led to deregulation of matrix remodelling enzymes, enhanced expression of growth factors and activation of the endothelin system. P4HI partially prevented deregulation of the MMP/TIMP system, inhibited upregulation of growth factors and normalized AoB-induced ECE-1 and ETB expression.
Conclusions: P4HI leads to an improvement of AoB-associated LV dysfunction and reduces imbalance of extracellular matrix turnover and hypertrophy-associated gene expression. P4H inhibition could therefore be of value in treatment of myocardial remodelling accompanying pressure overload hypertrophy.
Key Words: Aortic banding • Hypertrophy • Remodelling • Growth factors • Prolyl 4-hydroxylase
Received June 2, 2006; Revised July 21, 2006; Accepted October 9, 2006