Abstract
Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Angiotensin (Ang) IV possesses many biological properties that are not yet completely understood. Therefore, we investigated the function and mechanism of Ang IV in AMI in in vivo and in vitro conditions. AMI was performed by ligation of the left anterior descending coronary artery (LAD) in male C57 mice. Ang IV was continuously infused by a minipump 3 d before AMI for 33 d. The neonatal rat ventricular myocytes (NRVCs) were stimulated with Ang IV and cultured under hypoxic conditions. In vivo, Ang IV infusion significantly reduced the mortality after AMI. By the 7th day after AMI, compared with the AMI group, Ang IV reduced the inflammatory cytokine expression. Moreover, terminal deoxyribonucleotidyl transferase- (TDT-) mediated dUTP nick-end labeling (TUNEL) assay showed that Ang IV infusion reduced AMI-induced cardiomyocyte apoptosis. Compared with AMI, Ang IV reduced autophagosomes in cardiomyocytes and improved mitochondrial swelling and disarrangement, as assessed by transmission electron microscopy. By 30th day after AMI, Ang IV significantly reduced the ratio of heart weight to body weight. Echocardiography showed that Ang IV improved impaired cardiac function. Hematoxylin and eosin (H&E) and Masson staining showed that Ang IV infusion reduced the infarction size and myocardial fibrosis. In vitro, dihydroethidium (DHE) staining and comet assay showed that, compared with the hypoxia group, Ang IV reduced oxidative stress and DNA damage. Enzyme-linked immunosorbent assay (ELISA) showed that Ang IV reduced hypoxia-induced secretion of the tumor necrosis factor- (TNF-) ɑ and interleukin- (IL-) 1β. In addition, compared with the hypoxia group, Ang IV reduced the transformation of light chain 3- (LC3-) I to LC3-II but increased p62 expression and decreased cardiomyocyte apoptosis. Overall, the present study showed that Ang IV reduced the inflammatory response, autophagy, and fibrosis after AMI, leading to reduced infarction size and improved cardiac function. Therefore, administration of Ang IV may be a feasible strategy for the treatment of AMI.
Highlights
Acute myocardial infarction (AMI) is the most severe manifestation of the coronary artery disease (CAD) [1], which causes more than a third of deaths in developed nations annually and remains the leading cause of death worldwide [2]
The results indicated that Ang IV infusion played a protective role in MI
There was no significant difference among the four groups (Figure 1(b)), which suggested that the protective role of Ang IV was not associated with lipid levels
Summary
Acute myocardial infarction (AMI) is the most severe manifestation of the coronary artery disease (CAD) [1], which causes more than a third of deaths in developed nations annually and remains the leading cause of death worldwide [2]. Autophagy is a type of cell death that is closely associated with the development of heart failure [6]. It is a process in which the cytoplasmic constituents are sequestered in double-membraned autophagosomes and delivered to lysosomes for degradation [7]. Autophagy plays a critical role in maintaining the cardiomyocyte function and survival by removing the damaged organelles and protein aggregates [8]. Given the controversial role of autophagy during myocardial infarction (MI) and heart failure, a better understanding of the underlying molecular and cellular mechanisms is critical for preserving heart function after AMI
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