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Abstract
Calcific aortic valve disease (CAVD) is a progressive pathological condition with no effective pharmacological therapy. To identify novel molecular pathways as potential targets for pharmacotherapy, we studied microRNA (miRNA) profiles of heavily stenotic aortic valves (AS). One of the most upregulated miRNAs in AS valves compared to control valves was miR-125b (1.4-fold; P < 0.05). To identify CAVD-related changes in gene expression, DNA microarray analysis was performed, including an intermediate fibro(sclero)tic stage of the disease. This revealed changes especially in genes related to inflammation and immune response, including chemokine (C-C motif) ligand 3 (CCL3) and 4 (CCL4). CCL3 mRNA level was increased 3.9-fold (P < 0.05) when AS valves were compared to control valves, and a 2.5-fold increase (P < 0.05) in CCL4 gene expression was observed when fibro(sclero)tic valves were compared to control valves. Both CCL3 and CCL4 localized to macrophages by immunofluorescence. To identify chemokine–miRNA target pairs, data from miRNA target prediction databases were combined with valvular miRNA and mRNA expression profiles. MiR-125b was computationally predicted to target CCL4, as confirmed experimentally in cultured human THP-1 macrophages. Collectively, miR-125b and CCL4 appear to be involved in the progression of CAVD and may offer novel therapeutic and diagnostic strategies related to this disease.
Acknowledgements
We thank Dr Jussi Vuoristo for help with microarrays, and Kati Viitala, Manu Tuovinen, and Mari Jokinen for expert technical assistance.
Funding:
This study was supported by Academy of Finland Center of Excellence Funding (H.R. grant no. 266661) and the grants 276747 and 284504 (J.R.), the Finnish Foundation for Cardiovascular Research (J.R., H.R., P.O.), Paavo Nurmi Foundation, Ida Montin Foundation (P.O.), Orion Research Foundation (P.O.), Aarne Koskelo Foundation (P.O.), and Sigrid Jusélius Foundation (H.R.). The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.
Declaration of interest:
The authors report no conflicts of interest.
Supplementary material available online
Supplementary Methods and Supplementary Figures 1–6 to be found online at http://informahealthcare.com/doi/abs/10.3109/07853890.2015.1059955