Open AccessConditional deletion of RB1 in the Tie2 lineage leads to aortic valve regurgitation
Author(s) -
Marina Freytsis,
Lauren Baugh,
Zhiyi Liu,
Irene Georgakoudi,
Philip W. Hinds,
Lauren D. Black,
Gordon S. Huggins
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0190623
Subject(s) - extracellular matrix , aortic valve , conditional gene knockout , retinoblastoma protein , interstitial cell , biology , cardiology , medicine , cell , microbiology and biotechnology , cell cycle , genetics , gene , phenotype
Objective Aortic valve disease is a complex process characterized by valve interstitial cell activation, disruption of the extracellular matrix culminating in valve mineralization occurring over many years. We explored the function of the retinoblastoma protein (pRb) in aortic valve disease, given its critical role in mesenchymal cell differentiation including bone development and mineralization. Approach and results We generated a mouse model of conditional pRb knockout (cKO) in the aortic valve regulated by Tie2-Cre-mediated excision of floxed RB1 alleles. Aged pRb cKO animals showed significantly more aortic valve regurgitation by echocardiography compared to pRb het control animals. The pRb cKO aortic valves had increased leaflet thickness without increased cellular proliferation. Histologic studies demonstrated intense α-SMA expression in pRb cKO leaflets associated with disorganized extracellular matrix and increased leaflet stiffness. The pRb cKO mice also showed increased circulating cytokine levels. Conclusions Our studies demonstrate that pRb loss in the Tie2-lineage that includes aortic valve interstitial cells is sufficient to cause age-dependent aortic valve dysfunction.