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1 Internal Medicine, University of Virginia Health System, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: ckramer{at}virginia.edu.
Objective: The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in post-MI remodeling remains incompletely understood. Methods: We studied 5 groups of C57Bl/6 mice after 1 hour left anterior descending artery occlusion/reperfusion: 1. Wild type, untreated (n=12); 2. Wild-type, treated with the AT1-R blocker losartan (10-20 mg/kg/day in drinking water) from day 1-28 post-MI (n=10); 3. Cardiac overexpression of the AT2-R (AT2-TG, n=14); 4. AT2-TG treated with losartan (n=13) and 5. AT2-TG and null for the AT1a-R (AT2-TG/AT1KO, n=10). Cardiac magnetic resonance imaging (CMR) measured ejection fraction (EF) and LV end-diastolic and end-systolic volume (EDVI, ESVI) and mass indexed to weight on days 0, 1, 7, and 28 post-MI. Infarct size was measured on day 1 by late gadolinium enhanced CMR. Regional myocyte hypertrophy and collagen content were measured on day 28 post-MI. Results: Infarct size was similar amongst groups. Systolic blood pressure was lowest in AT2-TG/AT1KO. By Day 28 post-MI, when corrected for baseline differences, EDVI and ESVI were higher and EF lower in wild type than other groups. EF was highest and EDVI and mass index lowest in AT2-TG/AT1KO at day 28. The AT2-TG/AT1KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. Conclusions: The AT1-R and AT2-R are intricately intertwined in post-MI remodeling. Pharmacologic blockade of AT1-R is equivalent to AT2-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT1a-R is additive to AT2-R overexpression, due, at least in part, to blood pressure lowering.
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