Jornal Internacional de Pesquisa Cardiovascular

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

Sou Kishida, Hiroyuki Yamada, Noriyuki Wakana, Hiroyuki Kawahito, Daisuke Irie, Taku Kato, Masakazu Kikai, Kensuke Terada, Keita Yamamoto, Naotoshi Wada, Shinichiro Motoyama, Hiroki Takata, Hirokazu Yokoi, Yoshinori Tsubakimoto, Takehiro Ogata, Tomomi Ueyama and Satoaki Matoba

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.