Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats

Péter Bencsik, Krisztina Kupai, Z. Giricz, A. Görbe, Judit Pipis, Zsolt Murlasits, Gabriella F. Kocsis, Zoltán Varga-Orvos, L. Puskás, C. Csonka, T. Csont, P. Ferdinándy

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

We have previously shown that the inhibition of myocardial nitric oxide (NO) and peroxynitrite-matrix metalloproteinase (MMP) signaling by early preconditioning (PC) is involved in its cardioprotective effect. Therefore, in the present study, we investigated the role of NO and peroxynitrite-MMP signaling in the development of late PC. PC was performed by five consecutive cycles of 4-min coronary occlusion and 4-min reperfusion in anesthetized rats in vivo. Twenty-four hours later, hearts were subjected to a 30-min coronary occlusion followed by 180-min reperfusion to measure infarct size. In separate experiments, heart tissue was sampled to measure biochemical parameters before and 3, 6, 12, or 24 h after the PC protocol, respectively. Late PC decreased infarct size, increased cardiac inducible NO synthase (iNOS) activity and gene expression, and decreased SOD activity at 24 h significantly compared with sham-operated controls. Late PC increased cardiac superoxide levels significantly at 24 h; however, it did not change cardiac NO levels. Cardiac peroxynitrite levels were significantly decreased. Downstream cellular targets of peroxynitrite, MMP-2 and MMP-9 activities were decreased in the late PC group at 24 h compared with the sham-operated group. To verify if PC-induced inhibition of MMPs had a causative role in the reduction of infarct size, in separate experiments, we measured infarct size after the pharmacological inhibition of MMPs by ilomastat and found a significant reduction of infarct size compared with the vehicle-treated group. In conclusion, this is the first demonstration that the inhibition of cardiac peroxynitrite-MMP signaling contributes to cardioprotection by late PC and that pharmacological inhibition of MMPs is able to reduce infarct size in vivo. Furthermore, increased expression of iNOS may play a role in the development of late PC; however, increased iNOS activity does not lead to increased NO production in late PC.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number2
DOIs
Publication statusPublished - Aug 2010

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Myocardial Ischemic Preconditioning
Peroxynitrous Acid
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Nitric Oxide Synthase
Nitric Oxide
Coronary Occlusion
Reperfusion
Pharmacology
Matrix Metalloproteinase 9
Nitric Oxide Synthase Type II
Superoxides
Gene Expression

Keywords

  • Gene expression
  • Ilomastat
  • Inducible nitric oxide synthase
  • Nadph oxidase
  • Nitric oxide
  • Nitric oxide synthase
  • Nitrotyrosine
  • Peroxynitrite
  • Superoxide
  • Superoxide dismutase
  • Tissue inhibitors of metalloproteinase
  • Xanthine oxidoreductase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats. / Bencsik, Péter; Kupai, Krisztina; Giricz, Z.; Görbe, A.; Pipis, Judit; Murlasits, Zsolt; Kocsis, Gabriella F.; Varga-Orvos, Zoltán; Puskás, L.; Csonka, C.; Csont, T.; Ferdinándy, P.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 2, 08.2010.

Research output: Contribution to journalArticle

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AU - Pipis, Judit

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