Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling

The relative contribution of the angiotensin II type 1 and 2 receptors (AT₁-R and AT₂-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of 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^-1·day^-1 in drinking water) from day 1 to day 28 post-MI (n = 10); 3) cardiac overexpression of the AT₂-R [AT₂-transgenic (TG); n = 14]; 4) AT ₂-TG treated with losartan (n = 13); and 5) AT₂-TG and null for the AT_1a-R [AT₂-TG/AT₁ knockout (KO); n = 10]. Cardiac magnetic resonance imaging (CMR) measured ejection fraction and left ventricular end-diastolic and endsystolic volume (EDVI and 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. Infarct size was similar among 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 ejection fraction was lower in wild type than other groups. Ejection fraction was highest and EDVI and mass index were lowest in AT ₂-TG/AT₁KO at day 28. The AT₂-TG/AT ₁KO demonstrated less fibrosis in adjacent regions. Regional myocyte hypertrophy was similar in all groups. The AT₁-R and AT₂-R are intricately intertwined in post-MI remodeling. Pharmacological blockade of AT₁-R is equivalent to AT₂-R overexpression in attenuating post-MI remodeling. Genetic knockout of the AT_1a-R is additive to AT₂-R overexpression, due, at least in part, to blood pressure lowering.