Short-Term Treatment with an Angiotensin II Receptor Blocker Prevents Necrotic Core Formation by Inhibiting Oxidative Stress-Mediated Apoptosis in Macrophages

Short-Term Treatment with an Angiotensin II Receptor Blocker Prevents Necrotic Core Formation by Inhibiting Oxidative Stress-Mediated Apoptosis in Macrophages

Objective: To study the role of angiotensin II (Ang II) type 1 receptor (AT1R) on necrotic core formation associated with endoplasmic reticulum (ER) stress-induced macrophage apoptosis.

Methods and Results: Eight-week-old ApoE-deficient mice were fed a high-cholesterol diet and administered AT1R blocker (ARB), hydralazine, or vehicle from 15 weeks of age. Histochemical analysis of brachiocephalic artery at 19 weeks of age showed a marked reduction of necrotic core area in ARB-treated mice. At 17 weeks of age, mRNA expression levels of C/EBP Homologous Protein (CHOP) and the percentage of TUNEL-positive cells were also decreased in ARB-treated mice, concomitant with the significantly lower expressions of NOX2 and NOX4 genes. Free cholesterol (FC)-loaded thioglycollate-induced peritoneal macrophages (TGPM) showed a significant increase in CHOP mRNA expression and the number of annexin V- or propidium iodide (PI)-positive cells; however, these were not affected by cotreatment with Ang II or Ang II plus ARB. In contrast, TGPM isolated from Ang II-treated mice, exhibiting higher expression levels of NOX2 and p22phox genes, showed a more robust increase in CHOP mRNA expression after FC loading.

Conclusions: Our findings demonstrate that ARB treatment inhibits necrotic core formation, in part by alleviating oxidative stress-mediated amplification of ER stress-induced macrophage apoptosis.