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

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.

• Authors: Péter Bencsik, Krisztina Kupai, Zoltán Giricz, Anikó Görbe, Judit Pipis, Zsolt Murlasits, Gabriella F Kocsis, Zoltán Varga-Orvos, László G Puskás, Csaba Csonka, Tamás Csont, Péter Ferdinandy
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 299 Issue 2 Pg. H512-8 (Aug 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20543091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxamic Acids
• Indoles
• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors
• Superoxides
• Peroxynitrous Acid
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Superoxide Dismutase
• Matrix Metalloproteinase 2
• Mmp2 protein, rat
• Matrix Metalloproteinase 9
• ilomastat

Topics

• Animals
• Disease Models, Animal
• Enzyme Activation
• Hydroxamic Acids
• Indoles (pharmacology)
• Ischemic Preconditioning, Myocardial (methods)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinase Inhibitors
• Myocardial Infarction (enzymology, pathology, prevention & control)
• Myocardial Reperfusion Injury (enzymology, pathology, prevention & control)
• Myocardium (enzymology, pathology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Peroxynitrous Acid (metabolism)
• Protease Inhibitors (pharmacology)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Superoxide Dismutase (metabolism)
• Superoxides (metabolism)
• Time Factors
• Up-Regulation