Exploring a Functional Role for BMP10 in Heart Failure

PurposeCardiac fibrosis leads to adverse clinical outcomes in heart failure. Published studies have identified that bone morphogenetic protein-10 (BMP-10), a member of the transforming growth factor-b (TGB-b) superfamily, may form a heterodimer with BMP-9, which binds to the TGF-b co-receptor endoglin with high affinity and has been shown to limit cardiac fibrosis in heart failure. We hypothesized that a model of pressure overload-induced heart failure increases BMP-10 expression in the left ventricle, which limits cardiac fibrosis by increasing signaling via Smad1.MethodsAdult, male 10-week-old mice were subjected to transverse aortic constriction (TAC) using a 27G needle for all studies. C57 Bl/6 wild-type mice were subjected to TAC for 2 (acute) or 8 (chronic) weeks to quantify BMP-9 and BMP-10 expression. LV pressure-volume loop and echocardiographic data were obtained.ResultsA total of 6 mice underwent sham operations, 8 underwent 2-week TAC, and 8 underwent 8-week TAC. All mice survived until harvest. Compared to sham, there was a reduced ejection fraction and a dilated LV internal diastolic dimension in the chronic TAC cohort (Sham: 71±4 % v 8-week: 30±14%, p=0.001; Sham: 2.2±0.3 mm v 8-week: 3.8±0.6 mm, p=0.02). Additionally, compared to sham, both LV end-diastolic and end-systolic volumes were increased in the chronic TAC group (Sham: 57±11 uL v 8-week: 91±419 uL, p=0.02; Sham: 17±5 uL v 8-week: 64±23 uL, p=0.007). Compared to sham, minimum LV pressure was elevated in the chronic TAC cohort (Sham: -4.5±1.3 mmHg v 8-week: 8.8±10.3 mmHg, p= 0.04). BMP-10 mRNA expression was elevated in the right atrium, but reduced in the ventricles, at 8 weeks of TAC, while BMP-10 protein expression was increased at 8 weeks of TAC (Figure 1A-B). BMP-9 expression was reduced in the chronic TAC cohort in the left ventricle while endoglin levels were unchanged (Figure 1C).ConclusionBMP-10 mRNA levels are downregulated, while protein levels are upregulated, in the LV at 8 weeks of TAC. Further studies are needed to fully explore the functional role of BMP-10 in the heart. Cardiac fibrosis leads to adverse clinical outcomes in heart failure. Published studies have identified that bone morphogenetic protein-10 (BMP-10), a member of the transforming growth factor-b (TGB-b) superfamily, may form a heterodimer with BMP-9, which binds to the TGF-b co-receptor endoglin with high affinity and has been shown to limit cardiac fibrosis in heart failure. We hypothesized that a model of pressure overload-induced heart failure increases BMP-10 expression in the left ventricle, which limits cardiac fibrosis by increasing signaling via Smad1. Adult, male 10-week-old mice were subjected to transverse aortic constriction (TAC) using a 27G needle for all studies. C57 Bl/6 wild-type mice were subjected to TAC for 2 (acute) or 8 (chronic) weeks to quantify BMP-9 and BMP-10 expression. LV pressure-volume loop and echocardiographic data were obtained. A total of 6 mice underwent sham operations, 8 underwent 2-week TAC, and 8 underwent 8-week TAC. All mice survived until harvest. Compared to sham, there was a reduced ejection fraction and a dilated LV internal diastolic dimension in the chronic TAC cohort (Sham: 71±4 % v 8-week: 30±14%, p=0.001; Sham: 2.2±0.3 mm v 8-week: 3.8±0.6 mm, p=0.02). Additionally, compared to sham, both LV end-diastolic and end-systolic volumes were increased in the chronic TAC group (Sham: 57±11 uL v 8-week: 91±419 uL, p=0.02; Sham: 17±5 uL v 8-week: 64±23 uL, p=0.007). Compared to sham, minimum LV pressure was elevated in the chronic TAC cohort (Sham: -4.5±1.3 mmHg v 8-week: 8.8±10.3 mmHg, p= 0.04). BMP-10 mRNA expression was elevated in the right atrium, but reduced in the ventricles, at 8 weeks of TAC, while BMP-10 protein expression was increased at 8 weeks of TAC (Figure 1A-B). BMP-9 expression was reduced in the chronic TAC cohort in the left ventricle while endoglin levels were unchanged (Figure 1C). BMP-10 mRNA levels are downregulated, while protein levels are upregulated, in the LV at 8 weeks of TAC. Further studies are needed to fully explore the functional role of BMP-10 in the heart.