Moderate inhibition of myocardial matrix metalloproteinase-2 by ilomastat is cardioprotective

Bencsik, Péter; Pálóczi, János; Kocsis, Gabriella F.; Pipis, Judit; Belecz, István; Varga, Zoltán V.; Csonka, Csaba; Görbe, Anikó; Csont, Tamás; Ferdinándy, Péter

doi:10.1016/j.phrs.2013.12.007

Cited by 30 publications

(29 citation statements)

References 33 publications

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“…Finally, we confirmed in 3 WT hearts that DMSO at the used concentrations had not effect on I/R injury (Infarct size 57±2% and LDH 375±30 mU/mg, P = NS vs. WT_I/R) [5,10]. We also showed in 3 Mel-TG hearts that DMSO had no effect on damage (Infarct size 37±1% and LDH 215±25 U/mg ww, P = NS vs.…”

Section: Melusin Protection Depends On Activation Of Pi3k/akt and Erksupporting

confidence: 70%

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

et al. 2014

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Melusin is a muscle-specific protein which interacts with β1 integrin cytoplasmic domain and acts as chaperone protein. Its overexpression induces improved resistance to cardiac overload delaying left ventricle dilation and reducing the occurrence of heart failure. Here we investigated possible protective effect of melusin overexpression against acute ischemia/reperfusion (I/R) injury with or without Postconditioning cardioprotective maneuvers.Melusin-transgenic (Mel-TG) mice hearts were subjected to 30 minutes global ischemia followed by 60 minutes reperfusion. Interestingly, infarct size (IS) was reduced in Mel-TG mice hearts compared to wildtype (WT) hearts (40.3±3.5% Mel-TG vs. 59.5±3.8% WT hearts; n= 11 animals/group; P<0.05). The melusin protective effect was also demonstrated by measuring LDH release, which was 50% lower in Mel-TG compared to WT. Mel-TG hearts had a higher baseline level of AKT, ERK1/2 and GSK3β phosphorylation, and displayed increased phospho-kinases level after I/R compared to WT mice. Postischemic Mel-TG hearts displayed also increased levels of the antiapoptotic factor phospho-BAD.Importantly pharmacological inhibition of PI3K/AKT (Wortmannin) and ERK1/2 (U0126) pathways abrogated the melusin protective effect. Notably, HSP90, a chaperone known to protect heart from I/R injury, showed high levels of expression in the heart of Mel-TG mice suggesting a possible collaboration of this molecule with AKT/ERK/GSK3β pathways in the melusin-induced protection. Postconditioning, known to activate AKT/ERK/GSK3β pathways, significantly reduced IS and LDH release in WT hearts, but had no additive protective effects in Mel-TG hearts. These findings implicate melusin as an enhancer of AKT and ERK pathways and as a novel player in cardioprotection from I/R injury.

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Section: Melusin Protection Depends On Activation Of Pi3k/akt and Erksupporting

confidence: 70%

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

et al. 2014

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“…Giricz et al (2006) showed that by mimicking the moderate MMP2 inhibitory effect of preconditioning with the inhibitor ilomastat, cardioprotection occurred in both normal and hyperlipidemic hearts. Effective cardioprotection by a moderate inhibition of intracellular MMP2 was confirmed recently by Bencsik et al (2014). MMP2 inhibition as a pathway parallel to the known cardioprotective pathways has been confirmed by Bell et al (2013).…”

Section: B Hypertension Cardiac Hypertrophy and Remodelingmentioning

confidence: 82%

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

Ferdinándy¹,

Hausenloy²,

Heusch³

et al. 2014

Pharmacol Rev

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“…Sham‐operated animals were treated with the same procedure except occlusion of the coronary artery (Figure 1B). The surgical procedure was performed according to previous publications 20, 21…”

Section: Methodsmentioning

confidence: 99%

Adverse Effects on β‐Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long‐Term Cardiac Function

Schreckenberg

Bencsik

Weber

et al. 2017

JAHA

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BackgroundIschemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor‐mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of β‐adrenergic receptors and their effects on postischemic left ventricular function.Methods and ResultsThe β‐adrenergic signal transduction was analyzed in 3‐month‐old Wistar rats for each of the intervention strategies (Sham, ischemia/reperfusion, IPC, IPoC) immediately and 7 days after myocardial infarction. Directly after the infarction a cardioprotective potential was demonstrated for both IPC and IPoC: the infarct size was reduced, apoptosis and production of reactive oxygen species were lowered, and the myocardial tissue was preserved. Seven days after myocardial ischemia, only IPC hearts showed significant functional improvement. Along with a deterioration in fractional shortening, IPoC hearts no longer responded adequately to β‐adrenergic stimulation. The stabilization of β‐adrenergic receptor kinase‐2 via increased phosphorylation of Mdm2 (an E3‐ubiquitin ligase) was responsible for desensitization of β‐adrenergic receptors and identified as a characteristic specific to IPoC hearts.ConclusionsImmediately after myocardial infarction, rapid and transient activation of β‐adrenergic receptor kinase‐2 may be an appropriate means to protect the injured heart from excessive stress. In the long term, however, induction and stabilization of β‐adrenergic receptor kinase‐2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure.

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Moderate inhibition of myocardial matrix metalloproteinase-2 by ilomastat is cardioprotective

Cited by 30 publications

References 33 publications

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

Overexpression of the muscle-specific protein, melusin, protects from cardiac ischemia/reperfusion injury

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

Adverse Effects on β‐Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long‐Term Cardiac Function

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