Association between ACE2/ACE balance and pneumocyte apoptosis in a porcine model of acute pulmonary thromboembolism with cardiac arrest

Mol Med Rep. 2018 Mar;17(3):4221-4228. doi: 10.3892/mmr.2018.8426. Epub 2018 Jan 12.

Abstract

Acute pulmonary embolism (APE) is frequently reported in patients with cardiac arrest (CA) in emergency care. Pneumocyte apoptosis is commonly observed in the lungs following an APE. An important pathological mechanism evoking apoptosis during a lipopolysaccharide‑induced acute lung injury is the angiotensin‑converting enzyme 2 (ACE2)/ACE imbalance. The present study uses a porcine model to examine the anti‑apoptotic effects of captopril on APE‑CA and the return of spontaneous circulation (ROSC). Pigs were randomly assigned into four groups: Control, APE‑CA, ROSC‑saline, and ROSC‑captopril. Surviving pigs were euthanized at 6 h and lungs were isolated for analysis using several biochemical assays. Compared with the control group, the ACE2/ACE ratio was lower in the APE‑CA and ROSC pigs. In addition, APE‑CA pigs had higher Bcl‑2‑associated X protein (Bax) and cleaved caspase‑3 levels, and lower B‑cell lymphoma‑2 (Bcl‑2) level compared to control pigs. Captopril treatment reduced lung apoptosis, as demonstrated by lower TUNEL‑positive cells, higher Bcl‑2, and lower cleaved caspase‑3 protein levels in the lung. Notably, the ACE2/ACE ratio was positively correlated with Bcl‑2 protein levels and Bcl‑2/Bax ratio. In conclusion, captopril has a protective effect against lung apoptosis following ROSC and that maintaining the balance of the ACE2/ACE axis is important for inhibiting pulmonary apoptosis during APE.

Keywords: acute pulmonary embolism; cardiac arrest; return of spontaneous circulation; angiotensin-converting enzyme; lung apoptosis.

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / genetics
  • Acute Lung Injury / pathology
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / pathology
  • Angiotensin-Converting Enzyme 2
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Animals
  • Apoptosis / drug effects
  • Captopril / pharmacology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Heart Arrest / chemically induced
  • Heart Arrest / drug therapy*
  • Heart Arrest / genetics
  • Heart Arrest / pathology
  • Lipopolysaccharides
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pulmonary Embolism / chemically induced
  • Pulmonary Embolism / drug therapy*
  • Pulmonary Embolism / genetics
  • Pulmonary Embolism / pathology
  • Signal Transduction
  • Swine

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-bcl-2
  • Captopril
  • Peptidyl-Dipeptidase A
  • Angiotensin-Converting Enzyme 2
  • Caspase 3