Chymase inhibition reduces infarction and matrix metalloproteinase-9 activation and attenuates inflammation and fibrosis after acute myocardial ischemia/reperfusion.

Abstract

Chymase is activated after acute myocardial ischemia/reperfusion (AMI-R) and is associated with an early activation of matrix metalloproteinase-9 (MMP-9), which increases infarct size after experimental AMI, and late fibrosis. We assessed the effect of chymase inhibition on myocardial protection and early signs of fibrosis after AMI-R. Fourteen pigs underwent AMI-R and received intravenously either vehicle (V; n = 7) or chymase inhibitor (CM; n = 7). Separately, rat myocardial fibroblast was incubated with vehicle (n = 4), low-dose chymase (n = 4), high-dose chymase (n = 4), or high-dose chymase plus chymase inhibitor (n = 4). Infarct size (V, 41 ± 5; CM, 24 ± 5; P < 0.01) and serum troponin T (P = 0.03) at the end of reperfusion were significantly reduced in CM. Chymase activity in both the area at risk (AAR) (P = 0.01) and nonischemic area (P = 0.02) was significantly lower in CM. Myocardial levels of pro, cleaved, and cleaved/pro-MMP-9 in the AAR were significantly lower in CM than V (P < 0.01, < 0.01, and = 0.02, respectively), whereas phospho-endothelial nitric-oxide synthase (eNOS) (P < 0.01) and total eNOS (P = 0.03) were significantly higher in CM. Apoptotic cells (P = 0.05), neutrophils (P < 0.05), and MMP-9-colocalizing mast cells (P < 0.05) in the AAR were significantly reduced in CM. Interleukin-18 (P < 0.05) and intercellular adhesion molecule-1 (P < 0.05) mRNA levels were significantly lower in CM. In cultured cardiac fibrosis, Ki-67-positive cells were significantly higher in the high-dose chymase groups (P < 0.03). This study demonstrates that chymase inhibition plays crucial roles in myocardial protection related to MMP-9, inflammatory markers, and the eNOS pathway. It may also attenuate fibrosis induced by activated chymase after AMI-R.

• Authors: Shizu Oyamada, Cesario Bianchi, Shinji Takai, Louis M Chu, Frank W Sellke
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 1 Pg. 143-51 (Oct 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21795433 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Matrix Metalloproteinase Inhibitors
• Serine Proteinase Inhibitors
• Sulfonamides
• TY 51469
• Thiophenes
• C-Reactive Protein
• Nitric Oxide Synthase Type III
• Chymases

Topics

• Animals
• Blotting, Western
• C-Reactive Protein (analysis, metabolism)
• Cell Proliferation (drug effects)
• Chymases (antagonists & inhibitors)
• Cytokines (metabolism)
• Enzyme Activation (drug effects)
• Fibroblasts (drug effects)
• Fibrosis
• Hemodynamics (physiology)
• Inflammation (prevention & control)
• Male
• Matrix Metalloproteinase Inhibitors
• Myocardial Infarction (enzymology, etiology, prevention & control)
• Myocardial Reperfusion Injury (etiology, pathology, prevention & control)
• Myocardium (enzymology, pathology)
• Nitric Oxide Synthase Type III (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Serine Proteinase Inhibitors (pharmacology)
• Sulfonamides (pharmacology)
• Swine
• Swine, Miniature
• Thiophenes (pharmacology)