Pathological Role of Receptor for Advanced Glycation End Products in Calcified Aortic Valve Stenosis

Abstract

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs-RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age-matched and sex-matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls (P=0.004) and was significantly associated with a decreased ankle-brachial pressure index (P=0.007) and an increased intima-media thickness (P=0.026). RAGE and α-smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls (P=0.013 and P<0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement (P=0.012 and P=0.002, respectively). Conclusions Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.

Keywords: advanced glycation end products; aortic valve stenosis; atherosclerosis; calcification; inflammation; receptor for advanced glycation end products.

Figure 1. Expression of RAGE in calcified AS valves.

A, Expression of RAGE in calcified AS valves. *Left ventricle side. B, RAGE positive area (percentage) in calcified AS and controls (P=0.014). AS indicates aortic stenosis; Ca, calcification; and RAGE, receptor for advanced glycation end products.

Figure 2. Expression of SMCs in calcified AS valves.

A and B, Calcified aortic valve contained SMCs, which were mainly composed of SMemb‐positive or SM2‐positive cells (n=6). *Left ventricle side. AS indicates aortic stenosis; SM2, myosin heavy chain; SMCs, smooth muscle cells; and SMemb, nonmuscle myosin heavy chain.

Figure 3. αSMA and RAGE were colocalized, part of which were costained with ALP, osteocalcin, and SMemb in calcified aortic stenosis valves.

A and B, Immunofluorescence imaging of αSMA and RAGE in aortic stenosis patients (n=6) and controls (n=2). C, Immunofluorescent staining of ALP (n=5), osteocalcin (n=5), and SMemb (n=2) in aortic stenosis valves. TOPRO‐3 was used for nuclear staining. αSMA indicates α–smooth muscle actin; ALP, alkaline phosphatase; RAGE, receptor for advanced glycation end products; and SMemb, nonmuscle myosin heavy chain.