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Molecular mechanisms mediate roflumilast protective effect against isoprenaline-induced myocardial injury

Marwa Monier Mahmoud Refaie1, Manar Fouli Gaber Ibrahim2, Michael Atef Fawzy3

  • 1Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, Egypt.

Immunopharmacology and Immunotoxicology
|June 19, 2023
PubMed
Abstract

Insights

Roflumilast (ROF) protected against isoprenaline (ISO)-induced myocardial injury by modulating PDE4 and key signaling pathways. This treatment demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effects, offering a potential therapeutic strategy for heart damage.

Area of Science:

  • Cardiology
  • Pathology
  • Pharmacology

Background:

  • Myocardial necrosis is a prevalent cardiac disease with insufficient therapeutic options.
  • Investigating novel cardioprotective agents is crucial for managing myocardial injury.
  • Isoprenaline (ISO) is frequently used to induce experimental myocardial damage.

Purpose of the Study:

  • To evaluate the cardioprotective effects of roflumilast (ROF) against ISO-induced myocardial injury.
  • To elucidate the role of vascular endothelial growth factor/endothelial nitric oxide synthase (VEGF/eNOS) and cyclic guanosine monophosphate/cyclic adenosine monophosphate/ sirtuin1 (cGMP/cAMP/SIRT1) signaling pathways in ROF's protective mechanism.

Main Methods:

  • Animals were divided into control, ISO-induced injury, and ROF co-administered groups (three doses).
  • Cardiac injury was assessed by measuring biomarkers like troponin I, CK-MB, LDH, MDA, TNFα, cleaved caspase-3, and GSH.
  • VEGF, eNOS, cGMP, cAMP, and SIRT1 levels were quantified to evaluate signaling pathway involvement.

Main Results:

  • ISO administration significantly increased cardiac damage markers and induced histopathological changes.
  • ISO treatment led to decreased levels of antioxidants (GSH, TAC) and key signaling molecules (VEGF, eNOS, cGMP, cAMP, SIRT1).
  • Co-administration of ROF significantly ameliorated ISO-induced cardiac toxicity and normalized the measured parameters.

Conclusions:

  • Roflumilast (ROF) effectively reduced isoprenaline (ISO)-induced myocardial injury.
  • ROF's cardioprotective effects are linked to the modulation of PDE4, VEGF/eNOS, and cGMP/cAMP/SIRT1 signaling pathways.
  • The observed benefits include antioxidant, anti-inflammatory, and anti-apoptotic properties, highlighting ROF as a potential therapeutic agent.
Keywords:
Roflumilastcyclic adenosine monophosphatemyocardial injurysirtuin1vascular endothelial growth factor

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