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

Rutger J Hassink ^1*, Hidehiro Nakajima ², Hisako O Nakajima ², Pieter A Doevendans ¹ and Loren J Field ²

¹ Department of Cardiology, University Medical Center, Utrecht, Netherlands
² the Wells Center for Pediatric Research and Krannert Institute of Cardiology, Indiana University Sc, United States

^* To whom correspondence should be addressed. E-mail: rjhassink{at}ziggo.nl.

Accepted 28 April 2009

Abstract

Objective: Transgenic mice expressing the dominant interfering p193 protein in cardiomyocytes (MHC-1152stop mice) exhibit an induction of cell cycle activity and altered remodeling following experimental myocardial infarction (MI). We hypothesized that the altered remodeling would result in improved cardiac function in the MHC-1152stop mice following MI, as compared to 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 hrs and at 4 weeks post-MI, and left ventricular pressure-volume measurements were performed at 4 weeks post-MI in infarcted and sham-operated animals.

Results: Infarct size in MHC-1152stop mice and non-transgenic littermates was not statistically different at 24 hrs post-MI, as measured by tetrazolium staining. Morphometric analysis revealed that infarct scar expansion at 4 weeks post-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 post-MI ventricular isovolumic relaxation time constant (Tau) was decreased by 19% (p<0.05), and the slope of the dP/dtmax-EDV relationship was 99% increased (p<0.05), in infarcted MHC-1152stop mice as compared to infarcted non-transgenic littermates.

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