Abstract
Natriuretic peptide receptor-C (NPR-C/NPR-3) is a cell surface protein involved in vascular remodelling that is up-regulated in atherosclerosis. NPR-C expression has not been well characterized in human carotid artery occlusive lesions. We hypothesized that NPR-C expression correlates with intimal features of vulnerable atherosclerotic carotid artery plaque. To test this hypothesis, we evaluated NPR-C expression by immunohistochemistry (IHC) in carotid endarterectomy (CEA) specimens isolated from 18 patients. The grade, location, and co-localization of NPR-C in CEA specimens were evaluated using two tissue analysis techniques. Relative to minimally diseased CEA specimens, we observed avid NPR-C tissue staining in the intima of maximally diseased CEA specimens (65%; p=0.06). Specifically, maximally diseased CEA specimens demonstrated increased NPR-C expression in the superficial intima (61%, p=0.17), and deep intima (138% increase; p=0.05). In the superficial intima, NPR-C expression significantly co-localized with vascular smooth muscle cells (VSMCs) and macrophages. The intensity of NPR-C expression was also higher in the superficial intima plaque shoulder and cap regions, and significantly correlated with atheroma and fibroatheroma vulnerable plaque regions (β=1.04, 95% CI=0.46, 1.64). These findings demonstrate significant NPR-C expression in the intima of advanced carotid artery plaques. Furthermore, NPR-C expression was higher in vulnerable carotid plaque intimal regions, and correlate with features of advanced disease. Our findings suggest that NPR-C may serve as a potential biomarker for carotid plaque vulnerability and progression, in patients with advanced carotid artery occlusive disease.
Highlights
20% of all ischemic strokes result from an atherosclerotic embolic source located at the extra-cranial carotid artery bifurcation in the mid-neck region [1]
We initially evaluated Natriuretic peptide receptor-C (NPR-C) expression in maximally and minimally diseased carotid endarterectomy (CEA) specimens in a cohort of 5 patients who were non-diabetic and had high-grade asymptomatic carotid artery stenosis
Consistent with prior findings [20] whole-mount IHC demonstrated avid and diffuse NPR-C staining in maximally diseased CEA specimens (Figures 2A-2D)
Summary
20% of all ischemic strokes result from an atherosclerotic embolic source located at the extra-cranial carotid artery bifurcation in the mid-neck region [1]. More than 95% of patients with high-grade atherosclerotic carotid artery stenosis are asymptomatic [2,3,4] It is unclear what subset of patients have a vulnerable atherosclerotic carotid lesion that can lead to a stroke [4,5]. NPR-C activates cell signal transduction via guanine nucleotide regulatory protein activation and downstream MAP kinase and phospholipase-C signaling [13,14]. These pathways affect a wide variety of cell specific functions such as vascular smooth muscle cell (VSMC) hyperpolarization and relaxation [15], and inhibition of L-type calcium currents in cardiac myocytes [16]. These findings thereby implicate NPR-C in the regulation of vascular homeostatic functions and potentiation of atherosclerotic disease
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