Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure

التفاصيل البيبلوغرافية
العنوان: Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure
المؤلفون: Navin K. Kapur, Richard H. Karas, Vikram Paruchuri, Mark Aronovitz, Peter Natov, Kevin J. Morine, Xiaoying Qiao, Sam York, Yali Zhang
المصدر: Circulation. 138:513-526
بيانات النشر: Ovid Technologies (Wolters Kluwer Health), 2018.
سنة النشر: 2018
مصطلحات موضوعية: 0301 basic medicine, Cardiac function curve, medicine.medical_specialty, Cardiac fibrosis, GDF2, Haploinsufficiency, 030204 cardiovascular system & hematology, Article, Ventricular Function, Left, Smad1 Protein, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Physiology (medical), Internal medicine, Growth Differentiation Factor 2, medicine, Animals, Humans, Smad3 Protein, Phosphorylation, Heart Failure, Mice, Knockout, Ventricular Remodeling, biology, business.industry, Myocardium, Endoglin, Recovery of Function, Transforming growth factor beta, Fibroblasts, medicine.disease, Growth Differentiation Factors, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Heart failure, Bone Morphogenetic Protein 9, Cardiology, biology.protein, Cardiology and Cardiovascular Medicine, business, Signal Transduction
الوصف: Background: Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ coreceptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3, and, furthermore, that neutralizing endoglin activity promotes BMP9 activity. Methods: We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We used the transverse aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. Results: BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and a small interfering RNA approach. In BMP9 –/– mice subjected to transverse aortic constriction, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to transverse aortic constriction with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 in comparison with vehicle-treated controls. Because endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to transverse aortic constriction–induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3. Conclusions: Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis attributable to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.
تدمد: 1524-4539
0009-7322
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13decba3dde67dd198b3405ed50f1754Test
https://doi.org/10.1161/circulationaha.117.031635Test
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....13decba3dde67dd198b3405ed50f1754
قاعدة البيانات: OpenAIRE