ISSN: 2451-0629
Archives of Medical Science - Atherosclerotic Diseases
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Official journal of the International Lipid Expert Panel (ILEP)
vol. 5
Letter to the Editor

Cathepsin L in unstable plaques

Ayisha Z. Bashir

Doctoral student, Department of Biomechanics, University of Nebraska, Omaha, USA
Arch Med Sci Atheroscler Dis 2020; 5: e57–e63
Online publish date: 2020/05/21
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Bridging the gap between the pathogenesis of atherosclerosis, carotid plaques, and contributing to patient care is envisioned by incorporating bench research into technological interventions. Stroke is a massive public health problem, and in stroke care, immediate assessment and treatment are essential to reduce the risk of death and disability [1, 2]. However, many patients do not receive them due to lack of specialist services. Investigating the aetiology and underlying cause of stroke is key to prevention and rapid recovery. While health care professionals are using the latest technological interventions for the diagnosis and management of the stroke patient, the underlying pathology must be figured out, in order to bridge the gap between diagnosis and long-term care of the stroke patient. At least 20% of ischaemic strokes are caused by carotid artery atherosclerotic plaques [3, 4]. The determination of circulating inflammatory markers have the potential to identify individuals with symptomatic and unstable plaques [1, 5]. Patients with vulnerable plaques usually have a complex disease history and unpredictable road map of recovery. Plaques are made up of cholesterol, fatty substances, cellular waste products, calcium, and fibrin (a clotting material in the blood). The strength of the fibrous cap is important for plaque stability. Plaques vulnerable to rupture are characterised by a thin fibrous cap and a large lipid-rich necrotic core [4, 6]. Carotid plaque surface morphology can help to indicate plaque vulnerability because both surface irregularity and ulceration have been correlated with stroke [2]. Damage to the arteries’ inner walls seems to trigger inflammation and help plaque grow. Stable or asymptomatic plaques are rich in vascular smooth muscle cells (SMC), matrix, and collagen with few inflammatory cells, whereas unstable or symptomatic plaques that are prone to rupture contain few SMCs, more macrophages, and little collagen [5, 7]. Even though there are phenomenal gains in the clinical management of patients with symptomatic carotid artery disease, the molecular mechanisms and pathways leading to plaque instability remain poorly established. Identification of the molecular markers of plaque instability along with signalling mechanisms may help in providing alternatives to surgical treatment and prevention of stroke. Cathepsin L (CTSL) is an important lysosomal endopeptidase enzyme and is involved in the initiation of protein degradation. CTSL is one of the most potent elastases and collagenases [1, 6]. It is normally absent or minimally expressed in tissues including arteries. However, it is overexpressed in atherosclerotic lesions and CTSL expression in vascular cell types found CTSL, to be regulated by pro-inflammatory cytokines in these lesions (Figure 1). A pilot study consisting of quantitative immunohistochemical analysis of human carotid atherosclerotic lesions was conducted on human carotid endarterectomy tissues collected anonymously. Plaques were marked as clinically asymptomatic (A) and symptomatic (S) male and female patients, aged between 50 and 75 years. The protein expression of CTSL in S (unstable) plaques compared to A (stable) plaques was analysed by double immunofluorescence. The fibrous cap and necrotic core were assessed by morphometric analysis. Fibrous cap in S lesions were less than 65 μm and the necrotic core was thicker in symptomatic compared to asymptomatic plaques (n = 10) (S = 52 ±19 µm vs. A = 78 ±24 µm, p < 0.01). Thin fibrous cap was defined by Virmani et al. as one that is less than 65 µm thick, which was measured in our findings. Our initial findings through immunofluorescence studies showed increased expression of CTSL in symptomatic plaques (see supplementary data file). The increased expression of CTSL in S plaques validates the potential role of CTSL in plaque instability and needs further investigation. Cystatin C and transforming growth factor β1 (TGF-β1) showed expression in A plaques, while CTSL expression is reduced in these plaques. Cathepsin activity is shown to be involved in inflammation and the degradation of the extracellular matrix (ECM) in the fibrous cap, leading to the destabilisation of the plaque [6, 7]. Cathepsins degrade elastin, collagen, fibronectin, and laminin, and these proteases serve as potential markers for plaque inflammation and vulnerability [5, 7]. CTSL is an important lysosomal endopeptidase, which is involved in the initiation of protein degradation. CTSL is one of the most potent collagenases and elastases and is implicated in the progression of atherosclerotic plaque establishment, including the necrotic core formation and accumulation of monocytes and macrophages [7]. CTSL is involved in inflammation and degradation of the extracellular matrix in the fibrous cap, causing destabilisation of the plaque. Cystatin C, the endogenous inhibitor of CTSL is normally present in arteries while cathepsin L is not expressed in normal carotid arteries [6]. Significantly lower blood levels of TGF-β1 are detected in patients with atherosclerosis; paradoxically, studies indicate that TGF-β1 increases SMC cystatin C secretion [6, 8]. The imbalance in the expression between CTSL and their inhibitor Cyst C, along with TGF-β1, may favour proteolysis of ECM, leading to the pathogenesis of carotid artery disease and atherosclerosis [7, 8]. Therefore, the concentration of circulating levels of CTSL and their endogenous inhibitor Cyst C could be considered useful as a biomarker and indicator of carotid artery stenosis. Despite previous studies, at present it is still unclear how CTSL plays a role in the development of atherosclerotic plaque instability as well as plaque rupture and necrotic core formation [7]. In conclusion, even though the studies are ongoing, we are still gaining an understanding of the pathogenesis of CTSL interaction with cystatin-C and TGF-β1 and its relationship with carotid artery plaques in the hope that this could provide a novel therapy for plaque stabilisation. Monitoring circulating levels of CTSL, cystatin C, and TGF-β1 as biomarkers for vulnerable plaques is a unique and innovative future possibility to identify patients with a histologically unstable plaque. In patients with unstable plaques and carotid stenosis the risk of stroke is highest in the first few days and is low in asymptomatic patients with stable plaques [9, 10]. In addition to biomarkers, technological interventions using accessible imaging technology help in identification of patients with a higher or lower likelihood of an unstable carotid plaque (on histology) [10]. Because “time and tide wait for none”, the identification of plaque vulnerability and timely intervention is essential for the patient’s survival and recovery.


The research was made possible by the valuable insight and guidance of Dr. Devendra Agrawal; William J. Hunter, MD; the Faculty and Staff of the Clinical Translational Science Department, School of Medicine, Creighton University; Dr. Yiannis S. Chatzizisis (UNMC) and Dr. Sara Myers, Department of Biomechanics, University of Nebraska. This work was supported by research grant R01HL144125 to DK Agrawal from the NHLBI-NIH, USA.

Conflict of interest

The authors declare no conflict of interest.
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