scholarly journals Matrix Metalloproteinase-2 Inhibition in Acute Ischemia-Reperfusion Heart Injury—Cardioprotective Properties of Carvedilol

2021 ◽  
Vol 14 (12) ◽  
pp. 1276
Author(s):  
Monika Skrzypiec-Spring ◽  
Joanna Urbaniak ◽  
Agnieszka Sapa-Wojciechowska ◽  
Jadwiga Pietkiewicz ◽  
Alina Orda ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Matrix Metalloproteinase 2 ◽  
Acute Ischemia ◽  
Mechanical Function ◽  
Cardiac Contractile ◽  
Injury Group ◽  
Rat Hearts ◽  
Cardiac Contractile Dysfunction

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect against cardiac contractile dysfunction related with IR injury. Isolated rat hearts were subjected to either control aerobic perfusion or IR injury: 25 min of aerobic perfusion, followed by 20 min global, no-flow ischemia, and reperfusion for 30 min. The effects of carvedilol, nebivolol, or metoprolol were evaluated in hearts subjected to IR injury. Cardiac mechanical function and MMP-2 activity in the heart homogenates and coronary effluent were assessed along with troponin I content in the former. Only carvedilol improved the recovery of mechanical function at the end of reperfusion compared to IR injury hearts. IR injury induced the activation and release of MMP-2 into the coronary effluent during reperfusion. MMP-2 activity in the coronary effluent increased in the IR injury group and this was prevented by carvedilol. Troponin I levels decreased by 73% in IR hearts and this was abolished by carvedilol. Conclusions: These data suggest that the cardioprotective effect of carvedilol in myocardial IR injury may be mediated by inhibiting MMP-2 activation.

scholarly journals Intracellular Regulation of Matrix Metalloproteinase-2 Activity: New Strategies in Treatment and Protection of Heart Subjected to Oxidative Stress

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Grzegorz Sawicki
Keyword(s):  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Matrix Metalloproteinase 2 ◽  
Acid Oxidation ◽  
Intracellular Regulation ◽  
Heart Injury ◽  
New Strategies

Much is known regarding cardiac energy metabolism in ischemia/reperfusion (I/R) injury. Under aerobic conditions, the heart prefers to metabolize fatty acids, which contribute to 60–80% of the required ATP. During ischemia, anaerobic glycolysis increases and becomes an important source of ATP for preservation of ion gradients. With reperfusion, fatty acid oxidation quickly recovers and again predominates as the major source of mitochondrial oxidative metabolism. Although a number of molecular mechanisms have been implicated in the development of I/R injury, their relative contributions remain to be determined. One such mechanism involves the proteolytic degradation of contractile proteins, such as troponin I (TnI), myosin heavy chain, titin, and the myosin light chains (MLC1 and MLC2) by matrix metalloproteinase-2 (MMP-2). However, very little is known about intracellular regulation of MMP-2 activity under physiological and pathological conditions. Greater understanding of the mechanisms that govern MMP-2 activity may lead to the development of new therapeutic strategies aimed at preservation of the contractile function of the heart subjected to myocardial infarction (MI) or I/R. This review discusses the intracellular mechanisms controlling MMP-2 activity and highlights a new intracellular therapeutic direction for the prevention and treatment of heart injury.

scholarly journals Low Frequency Electromagnetic Field Conditioning Protects against I/R Injury and Contractile Dysfunction in the Isolated Rat Heart

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Dariusz Bialy ◽  
Magdalena Wawrzynska ◽  
Iwona Bil-Lula ◽  
Anna Krzywonos-Zawadzka ◽  
Mieczyslaw Wozniak ◽  
...  
Keyword(s):  
Electromagnetic Field ◽  
Coronary Flow ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Low Frequency ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Rate Pressure Product ◽  
Mechanical Function ◽  
Isolated Rat

Low frequency electromagnetic field (LF-EMF) decreases the formation of reactive oxygen species, which are key mediators of ischemia/reperfusion (I/R) injury. Therefore, we hypothesized that the LF-EMF protects contractility of hearts subjected to I/R injury. Isolated rat hearts were subjected to 20 min of global no-flow ischemia, followed by 30 min reperfusion, in the presence or absence of LF-EMF. Coronary flow, heart rate, left ventricular developed pressure (LVDP), and rate pressure product (RPP) were determined for evaluation of heart mechanical function. The activity of cardiac matrix metalloproteinase-2 (MMP-2) and the contents of coronary effluent troponin I (TnI) and interleukin-6 (IL-6) were measured as markers of heart injury. LF-EMF prevented decreased RPP in I/R hearts, while having no effect on coronary flow. In addition, hearts subjected to I/R exhibited significantly increased LVDP when subjected to LF-EMF. Although TnI and IL-6 levels were increased in I/R hearts, their levels returned to baseline aerobic levels in I/R hearts subjected to LF-EMF. The reduced activity of MMP-2 in I/R hearts was reversed in hearts subjected to LF-EMF. The data presented here indicate that acute exposure to LF-EMF protects mechanical function of I/R hearts and reduces I/R injury.

scholarly journals Inhibiting matrix metalloproteinase‐2 (MMP‐2 reduces endothelial damage in isolated rat hearts during ischemia‐reperfusion

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Justyna Fert‐Bober ◽  
Hernando Leon ◽  
Jolanta Sawicka ◽  
Paul Basran ◽  
Richard Schulz ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Endothelial Damage ◽  
Matrix Metalloproteinase 2 ◽  
Rat Hearts ◽  
Isolated Rat

scholarly journals Influence of ischemia/reperfusion and modulation of PI3K/Akt kinase pathway on matrix metalloproteinase-2 in rat hearts

2010 ◽  
Vol 29 (1) ◽  
pp. 31-40 ◽  
Author(s):  
A. Špániková ◽  
M. Ivanová ◽  
J. Matejíková ◽  
T. Ravingerová ◽  
M. Barančík
Keyword(s):  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Matrix Metalloproteinase 2 ◽  
Akt Kinase ◽  
Rat Hearts ◽  
Kinase Pathway

Inhibiting matrix metalloproteinase-2 reduces protein release into coronary effluent from isolated rat hearts during ischemia-reperfusion

2008 ◽  
Vol 103 (5) ◽  
pp. 431-443 ◽  
Author(s):  
Justyna Fert-Bober ◽  
Hernando Leon ◽  
Jolanta Sawicka ◽  
Rashpal S. Basran ◽  
Richard M. Devon ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Protein Release ◽  
Matrix Metalloproteinase 2 ◽  
Rat Hearts ◽  
Isolated Rat

scholarly journals Myocardial MMP-2 contributes to SERCA2a proteolysis during cardiac ischaemia–reperfusion injury

2019 ◽  
Author(s):  
Andrej Roczkowsky ◽  
Brandon Y H Chan ◽  
Tim Y T Lee ◽  
Zabed Mahmud ◽  
Bridgette Hartley ◽  
...  
Keyword(s):  
Muscle Relaxation ◽  
Matrix Metalloproteinase 2 ◽  
Contractile Dysfunction ◽  
Ischaemia Reperfusion Injury ◽  
Cardiac Contractile ◽  
Ischaemia Reperfusion ◽  
Rat Hearts ◽  
Cardiac Contractile Dysfunction ◽  
Isolated Rat

Abstract Aims Matrix metalloproteinase-2 (MMP-2) is a zinc-dependent protease which contributes to cardiac contractile dysfunction when activated during myocardial ischaemia–reperfusion (IR) injury. MMP-2 is localized to several subcellular sites inside cardiac myocytes; however, its role in the sarcoplasmic reticulum (SR) is unknown. The Ca2+ ATPase SERCA2a, which pumps cytosolic Ca2+ into the SR to facilitate muscle relaxation, is degraded in cardiac IR injury; however, the protease responsible for this is unclear. We hypothesized that MMP-2 contributes to cardiac contractile dysfunction by proteolyzing SERCA2a, thereby impairing its activity in IR injury. Methods and results Isolated rat hearts were subjected to IR injury in the presence or absence of the selective MMP inhibitor ARP-100, or perfused aerobically as a control. Inhibition of MMP activity with ARP-100 significantly improved the recovery of cardiac mechanical function and prevented the increase of a 70 kDa SERCA2a degradation fragment following IR injury, although 110 kDa SERCA2a and phospholamban levels appeared unchanged. Electrophoresis of IR heart samples followed by LC-MS/MS confirmed the presence of a SERCA2a fragment of ∼70 kDa. MMP-2 activity co-purified with SR-enriched microsomes prepared from the isolated rat hearts. Endogenous SERCA2a in SR-enriched microsomes was proteolyzed to ∼70 kDa products when incubated in vitro with exogenous MMP-2. MMP-2 also cleaved purified porcine SERCA2a in vitro. SERCA activity in SR-enriched microsomes was decreased by IR injury; however, this was not prevented with ARP-100. Conclusion This study shows that MMP-2 activity is found in SR-enriched microsomes from heart muscle and that SERCA2a is proteolyzed by MMP-2. The cardioprotective actions of MMP inhibition in myocardial IR injury may include the prevention of SERCA2a degradation.

scholarly journals Detecting Validated Intracellular ROS Generation with 18F-dihydroethidine-Based PET

2021 ◽  
Author(s):  
Edward C. T. Waters ◽  
Friedrich Baark ◽  
Zilin Yu ◽  
Filipa Mota ◽  
Thomas R. Eykyn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Contractile Function ◽  
Ex Vivo ◽  
Glutathione Depletion ◽  
Ros Generation ◽  
Cardiac Contractile ◽  
Rat Hearts ◽  
Intracellular Ros ◽  
Cardiac Contractile Dysfunction

Abstract Purpose To determine the sensitivity of the 18F-radiolabelled dihydroethidine analogue ([18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures The sensitivity of [18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [18F]DHE (50–150 kBq.min−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results [18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion [18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.

scholarly journals Distribution and activation of matrix metalloproteinase-2 in skeletal muscle fibers

2019 ◽  
Vol 317 (3) ◽  
pp. C613-C625 ◽  
Author(s):  
Xiaoyu Ren ◽  
Graham D. Lamb ◽  
Robyn M. Murphy
Keyword(s):  
Skeletal Muscle ◽  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Intracellular Localization ◽  
Muscle Fibers ◽  
Matrix Metalloproteinase 2 ◽  
Absolute Amount ◽  
Skinned Muscle ◽  
Functional Relevance

A substantial intracellular localization of matrix metalloproteinase 2 (MMP2) has been reported in cardiomyocytes, where it plays a role in the degradation of the contractile apparatus following ischemia-reperfusion injury. Whether MMP2 may have a similar function in skeletal muscle is unknown. This study determined that the absolute amount of MMP2 is similar in rat skeletal and cardiac muscle and human muscle (~10–18 nmol/kg muscle wet wt) but is ~50- to 100-fold less than the amount of calpain-1. We compared mechanically skinned muscle fibers, where the extracellular matrix (ECM) is completely removed, with intact fiber segments and found that ~30% of total MMP2 was associated with the ECM, whereas ~70% was inside the muscle fibers. Concordant with whole muscle fractionation, further separation of skinned fiber segments into cytosolic, membranous, and cytoskeletal and nuclear compartments indicated that ~57% of the intracellular MMP2 was freely diffusible, ~6% was associated with the membrane, and ~37% was bound within the fiber. Under native zymography conditions, only 10% of MMP2 became active upon prolonged (17 h) exposure to 20 μM Ca2+, a concentration that would fully activate calpain-1 in seconds to minutes; full activation of MMP2 would require ~1 mM Ca2+. Given the prevalence of intracellular MMP2 in skeletal muscle, it is necessary to investigate its function using physiological conditions, including isolation of any potential functional relevance of MMP2 from that of the abundant protease calpain-1.

scholarly journals Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 6990
Author(s):  
Kamilla Gömöri ◽  
Tamara Szabados ◽  
Éva Kenyeres ◽  
Judit Pipis ◽  
Imre Földesi ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Positive Control ◽  
Matrix Metalloproteinase 2 ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride

Background: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. Methods: Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. Results: MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. Conclusions: This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

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