Sclerostin ablation prevents aortic valve stenosis in mice

• Published in: American journal of physiology. Heart and circulatory physiology 2022-11, Vol.323 (5), p.H1037-H1047
• Main Authors: Joll, 2nd, J Ethan, Riley, Lance A, Bersi, Matthew R, Nyman, Jeffry S, Merryman, W David
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Aortic Valve - metabolism; Aortic Valve Stenosis - diagnosis; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - prevention & control; Calcinosis - genetics; Calcinosis - prevention & control; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Knockout; Osteoporosis - metabolism; Osteoporosis - pathology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00355.2022

The objective of this study was to test the hypothesis that targeting sclerostin would accelerate the progression of aortic valve stenosis. Sclerostin (mouse gene, ) is a secreted glycoprotein that acts as a potent regulator of bone remodeling. Antibody therapy targeting sclerostin is approved for osteoporosis but results from a clinical trial showed multiple off-target cardiovascular effects. Wild-type (WT, ) and -gene knockout-expression (Null, ) mice were generated and maintained to 12 mo of age on a high-cholesterol diet to induce aortic valve stenosis. Mice were examined by echocardiography, histology, and RNAseq. Immortalized valve interstitial cells were developed from each genotype for in vitro studies. Null mice developed a bone overgrowth phenotype, similar to patients with sclerosteosis. Surprisingly, however, WT mice developed hemodynamic signs of aortic valve stenosis, whereas Null mice were unchanged. WT mice had thicker aortic valve leaflets and higher amounts of α-smooth muscle actin, a marker myofibroblast activation and dystrophic calcification, with very little evidence of Runx2 expression, a marker of osteogenic calcification. RNAseq analysis of aortic roots indicated the HOX family of transcription factors was significantly upregulated in Null mice, and valve interstitial cells from Null animals were enriched with Hoxa1, Hoxb2, and Hoxd3 subtypes with downregulated Hoxa7. In addition, Null valve interstitial cells were shown to be less contractile than their WT counterparts. Contrary to our hypothesis, sclerostin targeting prevented hallmarks of aortic valve stenosis and indicates that targeted antibody treatments for osteoporosis may be beneficial for these patients regarding aortic stenosis. We have found that genetic ablation of the gene (protein: sclerostin) prevents aortic valve stenosis in aged, Western diet mice. This is a new role for sclerostin in the cardiovascular system. To the knowledge of the authors, this is one of the first studies directly manipulating sclerostin in a cardiovascular disease model and the first to specifically study the aortic valve. We also provide a potential new role for genes in cardiovascular disease, noting pan- upregulation in the aortic roots of sclerostin genetic knockouts. The role of genes in postnatal cardiovascular health and disease is another burgeoning field of study to which this article contributes.