title: Angiotensin IV protects cardiac reperfusion injury by inhibiting apoptosis and inflammation via AT4R in rats.
abstract: Angiotensin IV (Ang IV) is formed by aminopeptidase N from Ang III by removing the first N-terminal amino acid. Previously, we reported that Ang III has some cardioprotective effects against global ischemia in Langendorff heart. However, it is not clear whether Ang IV has cardioprotective effects. The aim of the present study was to evaluate the effect of Ang IV on myocardial ischemia-reperfusion (I/R) injury in rats. Before ischemia, male Sprague-Dawley rats received Ang IV (1mg/kg/day) for 3 days. Anesthetized rats were subjected to 45min of ischemia by ligation of left anterior descending coronary artery followed by reperfusion and then, sacrificed 1 day or 1 week after reperfusion. Plasma creatine kinase (CK) and lactate dehydrogenase (LDH) concentrations, and infarct size were measured. Quantitative analysis of apoptotic and inflammatory proteins in ventricles were performed using Western blotting. Pretreatment with Ang IV attenuated I/R-induced increases in plasma CK and LDH levels, and infarct size, which were blunted by Ang IV receptor (AT4R) antagonist and but not by antagonist for AT1R, AT2R, or Mas receptor. I/R increased Bax, caspase-3 and caspase-9 protein levels, and decreased Bcl-2 protein level in ventricles, which were blunted by Ang IV. I/R-induced increases in TNF-α, MMP-9, and VCAM-1 protein levels in ventricles were also blunted by Ang IV. Ang IV increased the phosphorylation of Akt and mTOR. These effects were attenuated by co-treatment with AT4R antagonist or inhibitors of downstream signaling pathway. Myocardial dysfunction after reperfusion was improved by Ang IV. These results suggest that Ang IV has cardioprotective effect against I/R injury by inhibiting apoptosis via AT4R and PI3K-Akt-mTOR pathway.
authors.affiliation: Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Byung Mun
authors.initials: BM
authors.lastname: Park
authors.affiliation: Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Seung Ah
authors.initials: SA
authors.lastname: Cha
authors.affiliation: Internal Medicine, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Physiology, Research Institute for Endocrine Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea. Electronic address: shkim@chonbuk.ac.kr.
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003402:Creatine Kinase / Q000097:blood; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology*
chemical_list: C090830:AT4 receptor; D000893:Anti-Inflammatory Agents; D002316:Cardiotonic Agents; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D003402:Creatine Kinase
keywords: Angiotensin IV; Apoptosis; Heart; Inflammation; Ischemia; Reperfusion; Signal pathway; Type 4 angiotensin receptor