Highlights • In addition to BMP2 and BMP4, BMP9 plays crucial, context-specific roles in the endothelium. • The recently coined ‘type III’ coreceptors interact with the type I and type II receptors ...and typically lead to endocytotic recycling of the BMP/BMP receptor complex. • BMPs activate different intracellular signaling cascades that play key roles in hypertension, vascular disorders, and atherosclerosis.
The Forkhead family of transcription factors mediates many aspects of physiology, including stress response, metabolism, commitment to apoptosis, and development. The Forkhead box subfamily O (FoxO) ...proteins have garnered particular interest due to their involvement in the modulation of cardiovascular biology. In this review, we discuss the mechanisms of FoxO regulation and outcomes of FoxO signaling under normal and pathological cardiovascular contexts.
Low-density lipoprotein receptor-related protein 1 (LRP1) regulates lipid and glucose metabolism in liver and adipose tissue. It is also involved in central nervous system regulation of food intake ...and leptin signalling. Here we demonstrate that endothelial Lrp1 regulates systemic energy homeostasis. Mice with endothelial-specific Lrp1 deletion display improved glucose sensitivity and lipid profiles combined with increased oxygen consumption during high-fat-diet-induced obesity. We show that the intracellular domain of Lrp1 interacts with the nuclear receptor Pparγ, a central regulator of lipid and glucose metabolism, acting as its transcriptional co-activator in endothelial cells. Therefore, Lrp1 not only acts as an endocytic receptor but also directly participates in gene transcription. Our findings indicate an underappreciated functional role of endothelium in maintaining systemic energy homeostasis.
Patients with chronic obstructive pulmonary disease, acute lung injury, and critical care illness may develop hypercapnia. Many of these patients often have muscle dysfunction which increases ...morbidity and impairs their quality of life. Here, we investigated whether hypercapnia leads to skeletal muscle atrophy. Mice exposed to high CO2 had decreased skeletal muscle wet weight, fiber diameter, and strength. Cultured myotubes exposed to high CO2 had reduced fiber diameter, protein/DNA ratios, and anabolic capacity. High CO2 induced the expression of MuRF1 in vivo and in vitro, whereas MuRF1−/− mice exposed to high CO2 did not develop muscle atrophy. AMP-activated kinase (AMPK), a metabolic sensor, was activated in myotubes exposed to high CO2, and loss-of-function studies showed that the AMPKα2 isoform is necessary for muscle-specific ring finger protein 1 (MuRF1) up-regulation and myofiber size reduction. High CO2 induced AMPKα2 activation, triggering the phosphorylation and nuclear translocation of FoxO3a, and leading to an increase in MuRF1 expression and myotube atrophy. Accordingly, we provide evidence that high CO2 activates skeletal muscle atrophy via AMPKα2-FoxO3a-MuRF1, which is of biological and potentially clinical significance in patients with lung diseases and hypercapnia.
Background: CO2 retention and skeletal muscle atrophy occur in patients with lung diseases and are associated with poor clinical outcomes.
Results: Hypercapnia leads to AMPK/FoxO3a/MuRF1-dependent muscle fiber size reduction.
Conclusion: Hypercapnia activates a signaling pathway leading to skeletal muscle atrophy.
Significance: High CO2 levels directly activate a proteolytic program of skeletal muscle atrophy which is of relevance to patients with lung diseases.
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