Activin type II receptor signaling in cardiac aging and heart failure
| Autor: | Christine E. Seidman, Se-Jin Lee, Jonathan G. Seidman, Sammy Elmariah, Federico Damilano, Nicholas E. Houstis, Anthony Rosenzweig, Vassilios J. Bezzerides, Vinita Chaudhari, Estelle Lach-Trifilieff, David J. Glass, Colin Platt, Jason D. Roh, Ryan Hobson, Chunyang Xiao, Ashish Yeri, Daniel A. Zlotoff, Mark D. Benson, Brian R. Lindman, Pablo A. Quintero, Robert E. Gerszten, Michael Biersmith |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Aging Activin Receptors Type II Activin Receptors Regulator Constriction Pathologic 030204 cardiovascular system & hematology Inbred C57BL Ligands Cardiovascular Severity of Illness Index Medical and Health Sciences Mice 0302 clinical medicine 80 and over Myocyte 2.1 Biological and endogenous factors Myocytes Cardiac Aetiology Receptor Aged 80 and over biology Frailty Chemistry General Medicine Activin receptor Middle Aged Biological Sciences Constriction Cell biology Ubiquitin ligase Activins Heart Disease Signal transduction Cardiac Signal Transduction Adult Proteasome Endopeptidase Complex Follistatin-Related Proteins Systole Heart Ventricles Type II Article Sarcoplasmic Reticulum Calcium-Transporting ATPases 03 medical and health sciences Pressure Animals Humans Aged Pressure overload Pathologic Heart Failure Myocytes Animal Myocardium Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology GDF11 Disease Models Proteolysis biology.protein |
| Zdroj: | Science translational medicine, vol 11, iss 482 |
| Popis: | Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF. |
| Databáze: | OpenAIRE |
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