Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques With Different Histopathological Characteristics
Abstract:Background and Purpose-Previous studies have shown that atherosclerotic lesions express a number of matrix metalloproteinases (MMPs). Here we investigated whether transcript levels of MMP-1, -3, -7, -9, and -12 in carotid atherosclerotic plaques were correlated with histological features and clinical manifestations. Methods-Atherosclerotic plaques (nϭ50) removed from patients undergoing carotid endarterectomy were classified histologically using a system proposed by Virmani et al, and MMP-1, -3, -7, -9, and -1… Show more
“…16 It localizes selectively to macrophages surrounding the lipid core 17 and is associated with decreased fibrous cap thickness, plaque rupture, and an increased risk of adverse cardiovascular events after endarterectomy. 18,19 Importantly, using a genome-wide age-at-onset informed approach, Traylor and …”
Objective—
Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
Approach and Results—
Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up.
Conclusions—
The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.
“…16 It localizes selectively to macrophages surrounding the lipid core 17 and is associated with decreased fibrous cap thickness, plaque rupture, and an increased risk of adverse cardiovascular events after endarterectomy. 18,19 Importantly, using a genome-wide age-at-onset informed approach, Traylor and …”
Objective—
Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus.
Approach and Results—
Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up.
Conclusions—
The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.
“…4 Atherosclerotic plaques also contain inflammatory cells such as macrophages that express and secrete cytokines. In addition, macrophages produce matrix metalloproteases (MMPs) in vulnerable plaques, 55,56 including the recently identified PAR1 agonist MMP-1. 15 Plaques that had been assessed as unstable because of a thin fibrous cap demonstrated 8-fold higher MMP-1 levels than lesions that harbor a thicker, more stable cap structure.…”
Section: Pars In Vascular Smooth Muscle Cells and Cardiomyocytesmentioning
confidence: 99%
“…15 Plaques that had been assessed as unstable because of a thin fibrous cap demonstrated 8-fold higher MMP-1 levels than lesions that harbor a thicker, more stable cap structure. 56 Therefore, targeting PAR1 downstream of MMP-1 may be efficacious in the control or reduction of plaque rupture in atherosclerotic disease. Cardiomyocytes also contain functional PAR1 and PAR2.…”
Section: Pars In Vascular Smooth Muscle Cells and Cardiomyocytesmentioning
Abstract-Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Thrombin signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. The thrombin receptors PAR1 and PAR4 can be effectively targeted in animals in which acute or prolonged exposure to thrombin leads to thrombosis and/or restenosis. In the present study, we describe the molecular and pharmacological basis of small-molecule inhibitors that target PAR1. In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling. Key Words: arteries Ⅲ endothelium Ⅲ inhibitors Ⅲ platelets Ⅲ receptors Ⅲ signal transduction Ⅲ thrombosis P rotease-activated receptors (PARs) play critical roles in coagulation, inflammation, and vascular homeostasis. [1][2][3][4][5] Proteases that are produced during vascular injury exert many of their cellular effects by cleaving and activating the PARs. Thrombin-dependent platelet activation and aggregation have been shown to be heightened in the setting of angioplasty and stenting, which may cause clinical complications including acute myocardial infarction and death. 6 -8 The high-affinity thrombin receptor PAR1 has long been recognized as an obvious candidate for therapeutic intervention in patients with acute coronary syndromes. It is not yet known, however, whether targeting only PAR1 will achieve sufficient therapeutic efficacy because of the presence of a more recently identified second thrombin receptor named PAR4. 9 -12 PAR1 and PAR2 (a trypsin but not a thrombin receptor) have also been shown to affect other cardiovascular functions such as vasoreactivity and cardiomyocyte hypertrophy.The purpose of the present review is to help the clinical reader understand why PARs are essential for the maintenance of normal vascular integrity. This review will focus on the potential therapeutic utility of targeting the PARs in thrombosis, atherosclerosis, and restenosis. Historically, the PARs have been recalcitrant to the development of peptidomimetic-based antagonists; however, recent PAR1 drug candidates based on natural products are now entering large-scale clinical trials for treatment of patients with acute coronary syndromes. In an orthogonal approach, PARs have also been blocked on the inside of the cell with the use of cell-penetrating pepducins that prevent signaling to internally located G proteins. [13][14][15][16][17] Proof-of-concept experiments in acute thrombosis models point to novel antiplatelet therapies that could potentially benefit patients at risk for acute thrombosis.
The Role of PARs in Normal Platelet FunctionPlatelets are essential for proper blood coagulation. Initiation of a platelet thromb...
“…También se ha descrito una fuerte correlación entre el porcentaje de núcleo lipídico ocupado por hemorragia y el porcentaje del perímetro del núcleo lipídico positivo para MMP-1 9 . Morgan y col demostraron mayor expresión genética de MMP-1 en placas con cáp-sula fina 30 . Guo y col describieron mayor concentración de MMP-1 en el tejido de placas rotas frente a las no rotas 10 .…”
Fundamento. Las placas ateroscleróticas que producen la mayoría de los síndromes coronarios agudos al romperse son los fibroateromas de cápsula fina, denominados placas vulnerables. Éstas pueden ser detectadas únicamente con técnicas invasivas de imagen intracoronaria. Es preciso encontrar un biomarcador no invasivo que permita identificar a los pacientes con estas placas sin necesidad de cateterismo cardiaco. La metaloproteinasa-1 es una enzima involucrada en el metabolismo de la matriz extracelular que ha sido relacionada con la ruptura de las placas ateroscleróticas. Se desconocen sus niveles séricos en pacientes con placas vulnerables.
Material y métodos.Se incluyeron pacientes sometidos a cateterismo cardiaco por enfermedad coronaria estable. Se estudiaron las arterias coronarias con tomografía de coherencia óptica para detectar placas vulnerables. Se extrajeron muestras de sangre periférica y del seno coronario para analizar la concentración de metaloproteinasa-1.resultados. Se incluyeron 51 pacientes. Trece tenían al menos un fibroateroma de cápsula fina. No se encontraron diferencias significativas en las características clínicas, perfil lipídico ni proteína C reactiva entre los pacientes con y sin placas vulnerables. Los pacientes con placas vulnerables presentaron concentraciones significativamente mayores de metaloproteinasa-1, tanto en sangre periférica (7330±5541 vs 2894±1783 pg/ml, p=0,025) como en seno coronario (6012±3854 vs 2707±1252 pg/ml, p=0,047).conclusiones. Los pacientes con placas vulnerables presentaron niveles séricos significativamente mayores de metaloproteinasa-1. Se requieren estudios con seguimiento clínico para evaluar el valor pronóstico de la metaloproteinasa-1 sérica.Palabras clave: Placa vulnerable. Fibroateroma de cápsula fina. Biomarcador. Metaloproteinasa-1. Síndrome coronario agudo.
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