2. Academic Validation
  3. Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling

Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling

  • Saudi Pharm J. 2024 Jul;32(7):102102. doi: 10.1016/j.jsps.2024.102102.
Noura Almusallam 1 2,  Asma Alonazi 1,  Anfal Bin Dayel 1,  Abdullah Almubarak 3,  Rizwan Ali 4,  Wajd Althakfi 5,  Rehab Ali 1,  Nouf Alrasheed 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 2 Pharmaceutical Care Department, King Saud Medical City, Ministry of Health, Riyadh 11196, Saudi Arabia.
  • 3 Experimental Surgery and Animal Laboratory, Prince Naif Bin Abdul Aziz Health Research Center, King Saud University, Riyadh 11451, Saudi Arabia.
  • 4 King Abdullah International Medical Research Center, Medical Research Core Facility and Platforms, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia.
  • 5 Department of Pathology, College of Medicine, KSUMC, King Saud University, Riyadh 11451, Saudi Arabia.
PMID: 39035363 DOI: 10.1016/j.jsps.2024.102102
Abstract

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-β (TGF-β). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-β1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3β. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, Animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase-MB (CK-MB) significantly increased by 40 %, troponin-I levels significantly increased by 25.4 %, and Lactate Dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-β1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-β1/Smad signalling pathway and restoring GSK-3β phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

Keywords

A740003; Fibrosis; GSK-3β; Myocardial infarction; P2X7-receptor; TGF-β1/Smad.

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