Cardioprotective effect of MMP-2-inhibitor-NO-donor hybrid against ischaemia/reperfusion injury

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Anna Krzywonos-Zawadzka1, Aleksandra Franczak1, Agnieszka Olejnik1

  • 1Department of Medical Laboratory Diagnostics, Division of Clinical Chemistry, Wroclaw Medical University, Wroclaw, Poland.

Journal of Cellular and Molecular Medicine
|February 8, 2019
PubMed

Insights

A novel hybrid compound protects the heart from ischemia/reperfusion injury by inhibiting matrix metalloproteinase 2 (MMP-2). This reduces contractile protein degradation, improving heart function and reducing tissue damage.

Area of Science:

  • Cardiovascular Science
  • Pharmacology
  • Biochemistry

Background:

  • Ischaemia/reperfusion (I/R) injury is a major cause of cardiovascular complications.
  • Matrix metalloproteinase 2 (MMP-2) degrades contractile proteins, contributing to heart injury during I/R.
  • Novel therapeutic strategies are needed to mitigate I/R-induced cardiac damage.

Purpose of the Study:

  • To investigate the protective effects of a novel MMP-2-inhibitor-NO-donor hybrid (5-phenyloxyphenyl-5-aminoalkyl nitrate barbiturate) against I/R injury in cardiac myocytes and rat hearts.
  • To assess the compound's impact on cardiac function, MMP-2 activity, and related molecular markers.

Main Methods:

  • Primary human cardiac myocytes and Wistar rat hearts were subjected to I/R.
  • The novel hybrid compound was administered in varying concentrations.
  • Evaluated hemodynamic parameters, tissue injury markers, MMP-2 activity, and expression of MMP-2, MMP-9, iNOS, and ADMA.

Main Results:

  • I/R significantly impaired heart function, reducing mechanical performance, coronary flow (CF), and heart rate (HR).
  • The hybrid compound dose-dependently restored mechanical function, CF, and HR.
  • Treatment reduced tissue injury, MMP-2 synthesis and activity, leading to decreased degradation of myosin light chains (MLCs) and improved myocyte contractility.
  • The hybrid also decreased inducible nitric oxide synthase (iNOS) expression and asymmetric dimethylarginine (ADMA) levels.

Conclusions:

  • 5-phenyloxyphenyl-5-aminoalkyl nitrate barbiturate demonstrates significant cardioprotective effects against I/R injury.
  • The compound's mechanism involves MMP-2 inhibition, preserving contractile proteins and improving cardiac function.
  • This novel hybrid represents a promising therapeutic agent for managing I/R-induced heart damage.
Keywords:
MMP-2-inhibitorcardioprotectionhybridnitric oxide donor

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