Characterization of the kallikrein-kinin system, metalloproteinases, and their tissue inhibitors in the in-stent restenosis after peripheral percutaneous angioplasty.
BACKGROUND
The kallikrein-kinin system (KKS) has several direct and indirect effects on cells and cellular mediators involved in the inflammatory process. Studies about inflammation on percutaneous transluminal angioplasty with stent (PTA/stent) to treat peripheral arterial disease (PAD) in humans are scarce. The matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases expressed in various cells and tissues such as fibroblasts, inflammatory cells, and, smooth muscle cells. Changes in the extracellular matrix (ECM) take place in the pathogenesis of many cardiovascular pathologies. MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are crucial in ECM remodeling in both physiologic and pathologic conditions. The aim of this study was to evaluate the role of the KKS and the MMP metabolism, which are important mediators that may contribute to tissue repair, in the process of arterial restenosis due to intimal hyperplasia in the femoropopliteal segment with the aim of developing new interventions.


METHODS
Thirty-nine consecutive patients were selected (regardless of ethnic group, age, or sex) for revascularization, who underwent PTA/stent of the femoropopliteal segment. Twenty-five patients with the same clinical characteristics who were scheduled for diagnostic angiography but not subjected to PTA/nitinol stent were also selected. The concentrations in blood of total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein was evaluated by the colorimetric method. Tissue kallikrein was evaluated by the spectrophotometric method. The activity of kininase II was measured by fluorometric analysis. Quantification of MMPs was performed by zymography, which is an electrophoresis technique, and TIMPs were measured by enzyme-linked immunosorbent assay.


RESULTS
Among the 31 patients who completed the survey, there were 10 cases of angiographically defined restenosis of >50%, and 21 cases without restenosis. There was an increase in the concentrations of the substrates (high-molecular-weight kininogens and lower molecular weight kininogens) and enzymes (plasma and tissue kallikrein) in patients with restenosis, indicating activation of this inflammatory pathway in these patients. The activity of kininase II was not significantly different between the groups of patients studied. There were no statistical differences between restenosis and no restenosis patients for both MMPs and TIMPs dosage, but there is an upward trend of MMPs in time 6 months in patients with restenosis.


CONCLUSIONS
With the aim of identifying factors contributing to restenosis after endovascular intervention, this study showed evidence of high activation of the KKS in the pathologic inflammatory process of PTA/stent restenosis. In the other hand, it could not show participation of metalloproteinase metabolism in PTA/stent restenosis.
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Maurício S
MS
Ribeiro
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Renata
R
Dellalibera-Joviliano
Departament of Pharmacology, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Christiane
C
Becari
Department of Biochemistry and Immunology, Ribeirão Preto Faculty of Medicine, University of Sao Paulo, Ribeirão Preto, São Paulo, Brazil.
Felipe Roberti
FR
Teixeira
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Paula Vasconcelos
PV
Araujo
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Carlos E
CE
Piccinato
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Cesar Presto
CP
Campos
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Paulo Roberto B
PR
Evora
Division of Vascular and Endovascular Surgery, Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address: eejov@fmrp.usp.br.
Edwaldo E
EE
Joviliano
D000368:Aged; D000800:Angioplasty, Balloon / Q000009:adverse effects / Q000295:instrumentation*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003251:Constriction, Pathologic; D005260:Female; D005263:Femoral Artery / Q000000981:diagnostic imaging; D006801:Humans; D006965:Hyperplasia; D007610:Kallikreins / Q000097:blood*; D007705:Kinins / Q000097:blood*; D008297:Male; D045726:Metalloproteases / Q000097:blood*; D008875:Middle Aged; D058426:Neointima; D058729:Peripheral Arterial Disease / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000628:therapy*; D011150:Popliteal Artery / Q000000981:diagnostic imaging; D011859:Radiography; D012008:Recurrence; D015607:Stents; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood*
D015415:Biomarkers; D007705:Kinins; D019714:Tissue Inhibitor of Metalloproteinases; D045726:Metalloproteases; D007610:Kallikreins