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

Anna Krzywonos‐Zawadzka,Mieczysław Woźniak,Aleksandra Franczak,Marek Radomski,Iwona Bil‐Lula,John F Gilmer,Agnieszka Olejnik,Grzegorz Sawicki

doi:10.1111/jcmm.14191

Abstract

Hypoxic injury of cardiovascular system is one of the most frequent complications following ischaemia. Heart injury arises from increased degradation of contractile proteins, such as myosin light chains (MLCs) and troponin I by matrix metalloproteinase 2 (MMP‐2). The aim of the current research was to study the effects of 5‐phenyloxyphenyl‐5‐aminoalkyl nitrate barbiturate (MMP‐2‐inhibitor‐NO‐donor hybrid) on hearts subjected to ischaemia/reperfusion (I/R) injury. Primary human cardiac myocytes and Wistar rat hearts perfused using Langendorff method have been used. Human cardiomyocytes or rat hearts were subjected to I/R in the presence or absence of tested hybrid. Haemodynamic parameters of heart function, markers of I/R injury, gene and protein expression of MMP‐2, MMP‐9, inducible form of NOS (iNOS), asymmetric dimethylarginine (ADMA), as well as MMP‐2 activity were measured. Mechanical heart function, coronary flow (CF) and heart rate (HR) were decreased in hearts subjected to I/R Treatment of hearts with the hybrid (1‐10 µmol/L) resulted in a concentration‐dependent recovery of mechanical function, improved CF and HR. This improvement was associated with decreased tissue injury and reduction of synthesis and activity of MMP‐2. Decreased activity of intracellular MMP‐2 led to reduced degradation of MLC and improved myocyte contractility in a concentration‐dependent manner. An infusion of a MMP‐2‐inhibitor‐NO‐donor hybrid into I/R hearts decreased the expression of iNOS and reduced the levels of ADMA. Thus, 5‐phenyloxyphenyl‐5‐aminoalkyl nitrate barbiturate protects heart from I/R injury.

Highlights

Revascularization and restoration of blood flow is a standard thera‐ peutic approach to ischaemia.[1,2] restoration of blood flow to previously ischemic myocardium may result in ischaemia/reperfusion (I/R) injury.[3]
The com‐ plete molecular basis for myocardial injury following I/R is not fully understood, it is known that degradation of contractile proteins by proteolytic enzymes is a major contributor to this process
As changes in the bioactiv‐ ity of the matrix metalloproteinase 2 (MMP‐2) and ni‐ tric oxide (NO) pathways may underlie I/R injury, we suggested that the administration of hybrid may normalize the levels of Matrix metalloproteinases (MMPs)‐2 and NO and ameliorate the impact of I/R on the heart

Summary

Introduction

Revascularization and restoration of blood flow is a standard thera‐ peutic approach to ischaemia.[1,2] restoration of blood flow to previously ischemic myocardium may result in ischaemia/reperfusion (I/R) injury.[3].

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Conclusion