Journal
ANTIOXIDANTS
Volume 11, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/antiox11091736
Keywords
ILK; nitric oxide; EndMT; calcific valve disease; endothelial dysfunction; aging
Funding
- Instituto de Salud Carlos III [PI20/00930]
- Junta de Comunidades de Castilla La Mancha (JCCM) [SBPLY/19/180501/000055]
- Universidad de Alcala [SBPLY/19/180501/000055]
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Calcific aortic valve disease (CAVD) is a common age-related disease. This study found that the expression of integrin-linked kinase (ILK) is downregulated in CAVD patients' aortic valves and is negatively correlated with valve calcification markers. Silencing ILK expression in valve endothelial cells promoted endothelial-to-mesenchymal transition (EndMT) and osteoblastic phenotype switch. Nitric oxide (NO) treatment prevented VEC transdifferentiation and calcification, suggesting the involvement of the ILK-eNOS signaling pathway in valve calcification.
Calcific aortic valve disease (CAVD) is highly prevalent during aging. CAVD initiates with endothelial dysfunction, leading to lipid accumulation, inflammation, and osteogenic transformation. Integrin-linked kinase (ILK) participates in the progression of cardiovascular diseases, such as endothelial dysfunction and atherosclerosis. However, ILK role in CAVD is unknown. First, we determined that ILK expression is downregulated in aortic valves from patients with CAVD compared to non-CAVD, especially at the valve endothelium, and negatively correlated with calcification markers. Silencing ILK expression in human valve endothelial cells (siILK-hVECs) induced endothelial-to-mesenchymal transition (EndMT) and promoted a switch to an osteoblastic phenotype; SiILK-hVECs expressed increased RUNX2 and developed calcified nodules. siILK-hVECs exhibited decreased NO production and increased nitrosative stress, suggesting valvular endothelial dysfunction. NO treatment of siILK-hVECs prevented VEC transdifferentiation, while treatment with an eNOS inhibitor mimicked ILK-silencing induction of EndMT. Accordingly, NO treatment inhibited VEC calcification. Mechanistically, siILK-hVECs showed increased Smad2 phosphorylation, suggesting a TGF-beta-dependent mechanism, and NO treatment decreased Smad2 activation and RUNX2. Experiments performed in eNOS KO mice confirmed the involvement of the ILK-eNOS signaling pathway in valve calcification, since aortic valves from these animals showed decreased ILK expression, increased RUNX2, and calcification. Our study demonstrated that ILK endothelial expression participates in human CAVD development by preventing endothelial osteogenic transformation.
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