Angiotensin II Type 2 Receptor Stimulation

Abstract

Background-This study is the first to examine the effect of direct angiotensin II type 2 (AT 2 ) receptor stimulation on postinfarct cardiac function with the use of the novel nonpeptide AT 2 receptor agonist compound 21 (C21). Methods and Results-Myocardial infarction (MI) was induced in Wistar rats by permanent ligation of the left coronary artery. Treatment with C21 (0.01, 0.03, 0.3 mg/kg per day IP) was started 24 hours after MI and was continued until euthanasia (7 days after MI). Infarct size was assessed by magnetic resonance imaging, and hemodynamic measurements were performed via transthoracic Doppler echocardiography and intracardiac Millar catheter. Cardiac tissues were analyzed for inflammation and apoptosis markers with immunoblotting and real-time reverse transcription polymerase chain reaction. C21 significantly improved systolic and diastolic ventricular function. Scar size was smallest in the C21-treated rats. In regard to underlying mechanisms, C21 diminished MI-induced Fas-ligand and caspase-3 expression in the peri-infarct zone, indicating an antiapoptotic effect. Phosphorylation of the p44/42 and p38 mitogen-activated protein kinases, both involved in the regulation of cell survival, was strongly reduced after MI but almost completely rescued by C21 treatment. Furthermore, C21 decreased MI-induced serum monocyte chemoattractant protein-1 and myeloperoxidase as well as cardiac interleukin-6, interleukin-1␤, and interleukin-2 expression, suggesting an antiinflammatory effect. Conclusions-Direct

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

“…Our recent observations indicate that anti-inflammatory mechanisms are attributable to AT2R-mediated cardioprotection (5). Taking into account that IL-10-mediated immunomodulation has been clearly shown to inhibit pathological processes in autoimmune diseases including MI (19), the present data support an unrecognized immune regulatory role of AT2R, reducing cardiac inflammatory injury by cardioprotective IL-10 via the CD8 + AT2R + T cells.…”

“…MI and treatment in male Wistar rats are performed as described previously (5). In brief, after left lateral thoracotomy, a suture was tightened around the proximal left anterior descending coronary artery.…”

“…Our recent data show that cardiac c-Kit + AT2R + cell population exists and concerns adaptive cardioprotection (8), raising the importance of other potential cellular mechanisms, which may also contribute to AT2R-mediated repair processes in the heart. Several previous studies have suggested that Ang II via its AT1R plays an important role in triggering inflammatory cardiovascular injury (4,5). Indeed, the cardioprotective effects of AT1R blockade are related to reduced myocardial inflammation in patients with MI (9).…”

“…A wealth of information indicates that the renin-angiotensin system can interfere with acute cardiac remodeling and inflammation processes during cardiovascular injury (4,5). Most of the cardiovascular actions of angiotensin II (Ang II), such as blood pressure and osmotic control, are mediated by AT1R (6).…”

“…Indeed, the cardioprotective effects of AT1R blockade are related to reduced myocardial inflammation in patients with MI (9). Accumulating experimental evidence from AT2R knockout mice or from rats under AT2R agonists further indicates that AT2R, which may be exposed to enhanced Ang II level after AT1R blockade, afford protection against MI-induced cardiac injury (5,10). Given the recent observations showing that angiotensin AT2R is abundantly expressed in immunocompetent cells and involved in cell-mediated inflammatory injury (11), it appears likely that AT2R exerts its actions through interfering with cellular inflammatory processes in the heart.…”