Ghrelin ameliorates cardiac fibrosis after myocardial infarction by regulating the Nrf2/NADPH/ROS pathway.

Abstract

To evaluate the role of ghrelin in cardiac fibrosis after myocardial infarction (MI) and to investigate the underlying mechanisms of ghrelin-regulated Nrf2/NADPH/ROS pathway-mediated cardioprotection, the profile of Nrf2, fibrosis markers, and oxidative stress markers were characterized in a rat model of MI and Angiotensin II (Ang II)-stimulated cardiac fibroblasts (CFs). The effects of ghrelin on cardiac function, fibrosis and oxidative stress were investigated after MI in vivo. The role of ghrelin in CF migration and proliferation was evaluated in Ang II-stimulated CFs in vitro. Inhibition of ghrelin receptors using the antagonist, d-Lys3-GHRP-6, in addition to ghrelin was employed in MI and CFs to investigate the direct effect of ghrelin on cardiac fibrosis. Loss function of Nrf2 in CFs was performed to investigate the effect of ghrelin-regulated Nrf2 on oxidative stress and cardiac fibrosis. Ghrelin improved the post-MI cardiac function and reduced cardiac fibrosis. This phenotype is associated with the upregulation of Nrf2 and downregulation of fibrotic proteins, NADPH oxidase and ROS production. In line with in vivo findings, ghrelin attenuated Ang II-stimulated CF migration, proliferation, and oxidative stress in vitro. Inhibition of the ghrelin receptor or knockdown of Nrf2 abolished the beneficial effects of ghrelin on MI or Ang II-stimulated cardiac fibroblasts. In conclusion, ghrelin ameliorates post-MI and Ang II-induced cardiac fibrosis by activating Nrf2, which in turn inhibits the NADPH/ROS pathway.

• Authors: Qian Wang, Ai-Dong Liu, Tian-Shu Li, Qian Tang, Xian-Cheng Wang, Xue-Bin Chen
• Journal: Peptides (Peptides) Vol. 144 Pg. 170613 (10 2021) ISSN: 1873-5169 [Electronic] United States
• PMID: 34314760 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• CCN2 protein, rat
• Cardiotonic Agents
• Ghrelin
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Reactive Oxygen Species
• Natriuretic Peptide, Brain
• Connective Tissue Growth Factor
• Malondialdehyde
• NADP
• Collagen
• NADPH Oxidases

Topics

• Animals
• Cardiotonic Agents (pharmacology)
• Cell Movement (drug effects, genetics)
• Collagen (metabolism)
• Connective Tissue Growth Factor (genetics)
• Fibroblasts (drug effects, metabolism)
• Fibrosis
• Ghrelin (pharmacology)
• Male
• Malondialdehyde (blood)
• Myocardial Infarction (drug therapy, metabolism, pathology)
• Myocardium (metabolism, pathology)
• NADP (metabolism)
• NADPH Oxidases (metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Natriuretic Peptide, Brain (blood)
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)