Semicarbazide-Sensitive Amine Oxidase Increases in Calcific Aortic Valve Stenosis and Contributes to Valvular Interstitial Cell Calcification

Abstract

Introduction. Calcific aortic valve stenosis (CAVS) is a common disease associated with aging. Oxidative stress participates in the valve calcification process in CAVS. Semicarbazide-sensitive amine oxidase (SSAO), also referred to as vascular adhesion protein 1 (VAP-1), transforms primary amines into aldehydes, generating hydrogen peroxide and ammonia. SSAO is expressed in calcified aortic valves, but its role in valve calcification has remained largely unexplored. The aims of this study were to characterize the expression and the activity of SSAO during aortic valve calcification and to establish the effects of SSAO inhibition on human valvular interstitial cell (VIC) calcification. Methods. Human aortic valves from n=80 patients were used for mRNA extraction and expression analysis, Western blot, SSAO activity determination, immunohistochemistry, and the isolation of primary VIC cultures. Results. SSAO mRNA, protein, and activity were increased with increasing calcification within human aortic valves and localized in the vicinity of the calcified zones. The valvular SSAO upregulation was consistent after stratification of the subjects according to cardiovascular and CAVS risk factors associated with increased oxidative stress: body mass index, diabetes, and smoking. SSAO mRNA levels were significantly associated with poly(ADP-ribose) polymerase 1 (PARP1) in calcified tissue. Calcification of VIC was inhibited in the presence of the specific SSAO inhibitor LJP1586. Conclusion. The association of SSAO expression and activity with valvular calcification and oxidative stress as well as the decreased VIC calcification by SSAO inhibition points to SSAO as a possible marker and therapeutic target to be further explored in CAVS.

Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas

“…Oxidative stress and chronic inflammation can be possible common denominators for TL shortening and early valve changes, since they may cause local telomere attrition and valve calcification ( Miller et al, 2008 ; Branchetti et al, 2013 ; De Meyer et al, 2018 ; Mercier et al, 2020 ). In fact, previous studies in atherosclerotic lesions, which exhibit similar oxidative stress and inflammation as stenotic aortic valves, reported the presence of shorter telomeres compared with healthy vessels ( Okuda et al, 2000 ; Matthews et al, 2006 ; Nzietchueng et al, 2011 ).…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…This suggests that uremia induces an impaired NRF2 system in CKD and hemodialysis (HD) patients, which contributes to the pathogenesis of oxidative stress and inflammation [27]. Importantly, increased oxidative stress and its sequalae are major contributors to premature atherosclerosis and calcification [28], resulting in increased cardiovascular (CV) morbidity and mortality in CKD [29,30]. Retained uremic toxins may further both become substrates for oxidative injury and increase the burden of oxidative stress [29,30].…”

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

“…Total of 100 ng total RNA was sent for array analysis. Valve gene expression data were obtained using Gene Chip Affymetrix human transcriptome 2.0 arrays (HTA 2.0, Santa Clara, CA, USA) and normalized with signal space transformation-robust multi-chip analysis (SST-RMA) using Expression Console (Affymetrix, Santa Clara, CA, USA), as previously described [24].…”