Original articles

Basic research

Expression of a transgene encoding mutant p193/CUL7 preserves cardiac function and limits infarct expansion after myocardial infarction

R J Hassink¹, H Nakajima², H O Nakajima², P A Doevendans¹, L J Field²

¹ Department of Cardiology, University Medical Centre, Utrecht, The Netherlands
² Wells Center for Pediatric Research and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, USA

Dr R J Hassink, Department of Cardiology, University Medical Centre, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands; rjhassink{at}ziggo.nl

Background: Transgenic mice expressing the dominant interfering p193 protein in cardiomyocytes (MHC-1152stop mice) exhibit an induction of cell cycle activity and altered remodelling after experimental myocardial infarction (MI).

Objective: To determine whether the altered remodelling results in improved cardiac function in the MHC-1152stop mice after MI, as compared with non-transgenic mice.

Methods: MHC-1152stop mice and non-transgenic littermates were subjected to experimental MI via permanent occlusion of the coronary artery. Infarct size was determined at 24 h and at 4 weeks after MI, and left ventricular pressure–volume measurements were performed at 4 weeks after MI in infarcted and sham-operated animals.

Results: Infarct size in MHC-1152stop mice and non-transgenic littermates was not statistically different at 24 h after MI, as measured by tetrazolium staining. Morphometric analysis showed that infarct scar expansion at 4 weeks after MI was reduced by 10% in the MHC-1152stop mice (p<0.05). No differences in cardiac function were detected between sham-operated MHC-1152stop mice and their non-transgenic littermates. However, at 4 weeks after MI, the ventricular isovolumic relaxation time constant () was decreased by 19% (p<0.05), and the slope of the dP/dt_max–EDV relationship was increased 99% (p<0.05), in infarcted MHC-1152stop mice as compared with infarcted non-transgenic littermates.

Conclusion: Expression of the dominant interfering p193 transgene results in a decrease in infarct scar expansion and preservation of myocardial function at 4 weeks after MI. Antagonism of p193 activity may represent an important strategy for the treatment of MI.

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