Blockage of Fibronectin 1 Ameliorates Myocardial Ischemia/Reperfusion Injury in Association with Activation of AMP-LKB1-AMPK Signaling Pathway.

Abstract

Myocardial ischemia/reperfusion injury (I/RI) is closely associated with energy substrate metabolism. Fibronectin 1 (Fn1) was markedly elevated in the heart of I/R pigs and ischemic patients, but its role in myocardial I/RI is controversial and the precise mechanism involved remains elusive. Herein, we tested whether blockage of Fn1 with its inhibitor (fibronectin tetrapeptide, RGDS) would alleviate myocardial I/RI. Wild-type (WT) mice were administered with RGDS once 3 h before I/R operation and once at 24 or 48 h postreperfusion, and sacrificed at 24 or 72 h post-I/R, respectively. Cardiac function was evaluated by echocardiography. Myocardial infarction size, apoptosis, fibrosis, and inflammation were examined via histological staining. Uptake of glucose and fatty acids were detected by positron emission tomography (PET) and computer tomography (CT) with [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and [18F]-fluoro-6-thia-heptadecanoic acid (FTHA), respectively. Our results showed that administration of RGDS to mice remarkably limited the I/R-induced myocardial infarct size, myocyte apoptosis, inflammation, oxidative stress, and fibrosis and improved cardiac contractile dysfunction. These protective effects were associated with upregulation of the AMP/ATP ratio and the activation of LKB1-AMPK signaling, which subsequently increased AS160-GLUT4-mediated glucose and fatty acid uptake, improved mitochondrial dynamic imbalance, and inactivated TGF-β and NF-κB signals in the I/R heart. In conclusion, the current study identified that blocking Fn1 protects against myocardial I/RI likely through activating the LKB1-AMPK-dependent signals and highlights that inhibition of Fn1 may be a novel therapeutic option for treating ischemic heart diseases.

• Authors: Yun-Long Zhang, Pang-Bo Li, Xiao Han, Bo Zhang, Hui-Hua Li
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2022 Pg. 6196173 ( 2022) ISSN: 1942-0994 [Electronic] United States
• PMID: 35602095 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Yun-Long Zhang et al.

Chemical References

• Fibronectins
• Adenosine Monophosphate
• AMP-Activated Protein Kinases
• Glucose

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adenosine Monophosphate (therapeutic use)
• Animals
• Fibronectins
• Fibrosis
• Glucose (metabolism)
• Inflammation
• Mice
• Myocardial Infarction (pathology)
• Myocardial Reperfusion Injury (metabolism)
• Signal Transduction