2014

DOI: 10.1161/circresaha.114.302355

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Atherosclerotic Plaque Destabilization

Carlos Silvestre-Roig

¹

,

Menno P.J. de Winther

²

,

Christian Weber

³

et al.

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Matrix Metalloproteinase (Mmp)-9 In Coronary Artery Disease1

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Cited by 259 publications

(105 citation statements)

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“…Additionally, our identification of plaque macrophages leads us to believe that the statin treatment has a direct effect on inflammation at the cellular level. The statin treatment significantly reduced macrophage invasion, which is a key contributor to plaque vulnerability 36, 37…”

Section: Discussionmentioning

confidence: 99%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

¹

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et al. 2016

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

“…Additionally, our identification of plaque macrophages leads us to believe that the statin treatment has a direct effect on inflammation at the cellular level. The statin treatment significantly reduced macrophage invasion, which is a key contributor to plaque vulnerability 36, 37…”

Section: Discussionmentioning

confidence: 99%

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

¹

,

²

,

³

et al. 2016

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BackgroundAlthough clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques.Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01).ConclusionsResults of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

“…Atherosclerosis is a chronic inflammatory process in the arterial wall (Silvestre-Roig et al 2014). As a mediator of inflammation and matrix-degrading protease, matrix metalloproteinase (MMP)-9 is considered to play a key role in both development of atherosclerosis and plaque destabilization.…”

Section: Matrix Metalloproteinase (Mmp)-9 In Coronary Artery Diseasementioning

confidence: 99%

Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol

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²

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³

et al. 2016

Psychoneuroendocrinology

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Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol, Psychoneuroendocrinology, 2016. 73() AbstractStress and inflammation are both important risk factors for coronary artery disease (CAD). However, the susceptibility to stress-induced inflammation and its determinants have been little explored in patients with CAD. Here, our aim was to study the stress-induced inflammatory response, more precisely the early release of matrix metalloproteinase (MMP)-9, and its association with cortisol response in patients with CAD. Sixty-four patients underwent a standardized laboratory stress test.The stress-induced release of MMP-9 was closely associated with the release of other neutrophilassociated proteins, MMP-8 and myeloperoxidase (MPO). It also showed a large variation among patients, as did cortisol. Twenty minutes after stress, a negative association between changes in MMP-9 and cortisol was seen (p<0.01). In vitro, dexamethasone reduced the IL-8-mediated release of MMP-9 from neutrophils, indicating that glucocorticoids may exert rapid effects on neutrophil activation. Further characterization of patients revealed that stress-induced release of MMP-9 was related to leukocyte telomere shortening and increased ultrasound-assessed plaque occurrence in the carotid arteries, but not to other characteristics such as age, gender or psychological background factors. The susceptibility to stress-induced release of MMP-9 may thus have impact on disease phenotype. Stress tests can be useful to identify CAD patients in need of novel prevention and treatment strategies.

“…Activated lesional macrophages release cytokines, chemokines, and matrix metalloproteinases, with the latter digesting extracellular matrix components and thus leading to plaque destabilization. Finally, macrophages die as a consequence of intracellular lipid accumulation and hence contribute to necrotic core formation in advanced plaques [3, 7]. The persistent inflammation is a key characteristic of atherosclerosis and an important factor of leukocyte recruitment for the initiation and progression of lesion development.…”

Section: Introductionmentioning

confidence: 99%

The Ins and Outs of Myeloid Cells in Atherosclerosis

2018

J Innate Immun

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Atherosclerosis is a chronic inflammation of the arterial vessel wall that arises from an imbalanced lipid metabolism. A growing body of literature describes leukocyte recruitment as a critical step in the initiation and progression of lesion development. By contrast, the role of leukocytes during plaque regression has been described in less detail. Leukocyte egress might be an important step to resolving chronic inflammation and therefore it may be a promising target for limiting advanced lesion development. This review aims to summarize our current knowledge of leukocyte recruitment to the arterial vessel wall. We will discuss mechanisms of leukocyte egress from the lesion site, as well as potential therapeutic strategies to promote atherosclerotic regression.

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