title: 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.affiliation: Cardiovascular Research Center, Division of Cardiothoracic Surgery, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
authors.forename: Shizu
authors.initials: S
authors.lastname: Oyamada
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Louis M
authors.initials: LM
authors.lastname: Chu
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D053818:Chymases / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D006439:Hemodynamics / Q000502:physiology; D007249:Inflammation / Q000517:prevention & control*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C524344:TY 51469; D013876:Thiophenes; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; D053818:Chymases