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The objective of this study was to test the hypothesis that targeting sclerostin would accelerate the progression of aortic valve stenosis. Sclerostin (mouse gene, Sost ) 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 stage III clinical trial showed multiple off-target cardiovascular effects. Wild-type (WT, Sost +/+ ) and Sost -gene knockout-expression (Null, Sost -/- ) 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. NEW & NOTEWORTHY We have found that genetic ablation of the Sost 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 Hox genes in cardiovascular disease, noting pan- Hox upregulation in the aortic roots of sclerostin genetic knockouts. The role of Hox genes in postnatal cardiovascular health and disease is another burgeoning field of study to which this article contributes.

Pressure overload of the heart is characterized by concentric hypertrophy and interstitial fibrosis. Cardiac fibroblasts (CFs) in the ventricular wall become activated during injury and synthesize and compact the extracellular matrix, which causes interstitial fibrosis and stiffening of the ventricular heart walls. Talin1 (Tln1) and Talin2 (Tln2) are mechanosensitive proteins that participate in focal adhesion transmission of signals from the extracellular environment to the actin cytoskeleton of CFs. The aim of the present study was to determine whether the removal of Tln1 and Tln2 from CFs would reduce interstitial fibrosis and cardiac hypertrophy. Twelve-week-old male and female Tln2-null ( Tln2 -/- ) and Tln2-null, CF-specific Tln1 knockout ( Tln2 -/- ; Tln1 CF-/- ) mice were given angiotensin-II (ANG II) (1.5 mg/kg/day) or saline through osmotic pumps for 8 wk. Cardiomyocyte area and measures of heart thickness were increased in the male ANG II-infused Tln2 -/- ; Tln1 CF-/- mice, whereas there was no increase in interstitial fibrosis. Systolic blood pressure was increased in the female Tln2 -/- ; Tln1 CF-/- mice after ANG II infusion compared with the Tln2 -/- mice. However, there was no increase in cardiac hypertrophy in the Tln2 -/- ; Tln1 CF-/- mice, which was seen in the Tln2 -/- mice. Collectively, these data indicate that in male mice, the absence of Tln1 and Tln2 in CFs leads to cardiomyocyte hypertrophy in response to ANG II, whereas it results in a hypertrophy-resistant phenotype in female mice. These findings have important implications for the role of mechanosensitive proteins in CFs and their impact on cardiomyocyte function in the pathogenesis of hypertension and cardiac hypertrophy. NEW & NOTEWORTHY The role of talins has been previously studied in cardiomyocytes; however, these mechanotransductive proteins that are members of the focal adhesion complex have not been examined in cardiac fibroblasts previously. We hypothesized that loss of talins in cardiac fibroblasts would reduce interstitial fibrosis in the heart with a pressure overload model. However, we found that although loss of talins did not alter fibrosis, it did result in cardiomyocyte and ventricular hypertrophy.