NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension
AbstractAim: The present study investigates the role of NF-κB in Bmpr2-related pulmonary hypertension (PH) using a murine model of PH with inducible overexpression of a cytoplasmic tail Bmpr2 mutation. Methods and Results: Electrophoretic mobility shift assay for nuclear extracts in Bmpr2R899X mouse lung and immunohistochemistry for NF-κB p65 in human PAH lung demonstrate that NF-κB is activated in end-stage disease. Acute inflammation or expression of a constitutively active NF-κB elicits a strong suppression of the BMP pathway in mice inversely correlating to activation of NF-κB targets. However, Bmpr2 mutation does not result in NF-κB activation in early disease development as assessed by luciferase reporter mice. Moreover, Bmpr2 mutant mice in which NF-κB activation is genetically blocked develop PH indistinguishable from that without the block. Finally, delivery of a virus causing NF-κB activation strongly exacerbates development of PH in Bmpr2 mutant mice, associated with increased remodeling. Conclusion: NF-κB activation exacerbates, but is not required for Bmpr2-related PH. Pulmonary vascular-specific activation of NF-κB may be a “second hit” that drives penetrance in heritable PH. View Full-Text
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Talati, M.; Mutlak, H.; Lane, K.B.; Han, W.; Hemnes, A.; Mutlak, O.; Blackwell, T.; Zaynagetdinov, R.; Blackwell, T.S.; West, J. NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension. Diseases 2014, 2, 148-167.
Talati M, Mutlak H, Lane KB, Han W, Hemnes A, Mutlak O, Blackwell T, Zaynagetdinov R, Blackwell TS, West J. NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension. Diseases. 2014; 2(2):148-167.Chicago/Turabian Style
Talati, Megha; Mutlak, Haitham; Lane, Kirk B.; Han, Wei; Hemnes, Anna; Mutlak, Outi; Blackwell, Tom; Zaynagetdinov, Rinat; Blackwell, Timothy S.; West, James. 2014. "NF-κB Activation Exacerbates, but Is not Required for Murine Bmpr2-Related Pulmonary Hypertension." Diseases 2, no. 2: 148-167.