Submitted on August 29, 2007
Accepted on October 5, 2007
Interaction Between Bradykinin Subtype 2 and Angiotensin II Type 2 Receptors During Post-MI Left Ventricular Remodeling
David C Isbell1, Szilard Voros1, Zequan Yang2, Joseph M DiMaria3, Stuart S Berr3, Brent A. French4, Frederick H Epstein3, Sanford P Bishop5, Hongkun Wang6, Rene J Roy3, Brandon A Kemp1, Hiroaki Matsubara7, Robert M. Carey1, and Christopher Kramer8*
1 Medicine, University of Virginia Health System, Charlottesville, Virginia, United States
2 Biomedical Engineering, University of Virginia Health System, United States
3 Radiology, University of Virginia Health System, Charlottesville, Virginia, United States
4 Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia, United States
5 Pathology, University of Alabama, Birmingham, Birmingham, Alabama, United States
6 Public Health Services, University of Virginia Health System, Charlottesville, Virginia, United States
7 Cardiovascular Medicine, Kyoto Prefectural University, Japan
8 Radiology and Medicine, University of Virginia Health System, Charlottesville, Virginia, United States
* To whom correspondence should be addressed. E-mail: ckramer{at}virginia.edu.
Background: AT2-receptor overexpression (AT2TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT2TG are mediated via the bradykinin-2 receptor (B2R).
Methods and Results: Fourteen transgenic mice overexpressing the AT2R (AT2TG), 10 mice with a B2R deletion (B2KO), 13 AT2TG with B2R deletion (AT2TG/B2KO), and 11 wild type (WT) mice were studied. All mice were on a C57BL/6 background. Mice were studied by cardiac magnetic resonance imaging (CMR) at baseline and days 1, 7, and 28 post-MI induced by 1 hour of occlusion of the left anterior descending artery followed by reperfusion. Short axis images from apex to base were used to compare ventricular volumes and ejection fraction (EF). At baseline, end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) were lower and EF higher in AT2TG compared to the other 3 strains. Infarct size was similar between groups. No differences were observed in global remodeling parameters at day 28 between AT2TG and AT2TG/B2KO; however, EDVI and ESVI were lower and EF higher in both transgenic groups than in WT or B2KO. Both strains lacking B2R demonstrated increased collagen content and less hypertrophy in adjacent noninfarcted regions at day 28.
Conclusion: Attenuation of post-infarct remodeling by overexpression of AT2R is not directly mediated via a B2R pathway. However, B2R does appear to have a role in the smaller cavity size and hyperdynamic function observed at baseline in AT2TG and in limiting collagen deposition during post-infarct remodeling.
