BCL11B regulates arterial stiffness and related target organ damage
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Date
2021-03-19
Authors
Valisno, Jeff Arni C.
May, Joel
Singh, Kuldeep
Helm, Eric Y.
Venegas, Lisia
Budbazar, Enkhjargal
Goodman, Jena B.
Nicholson, Christopher J.
Avram, Dorina
Cohen, Richard A.
Version
Published version
OA Version
Citation
J.A.C. Valisno, J. May, K. Singh, E.Y. Helm, L. Venegas, E. Budbazar, J.B. Goodman, C.J. Nicholson, D. Avram, R.A. Cohen, G.F. Mitchell, K.G. Morgan, F. Seta. 2021. "BCL11B Regulates Arterial Stiffness and Related Target Organ Damage." Circulation Research, Volume 128, Issue 6, pp.755-768. https://doi.org/10.1161/CIRCRESAHA.120.316666
Abstract
RATIONALE: BCL11B (B-cell leukemia 11b) is a transcription factor known as an essential regulator of T lymphocytes and neuronal development during embryogenesis. A genome-wide association study showed that a gene desert region downstream of BCL11B, known to function as a BCL11B enhancer, harbors single nucleotide polymorphisms associated with increased arterial stiffness. However, a role for BCL11B in the adult cardiovascular system is unknown.
OBJECTIVE: Based on these human findings, we sought to examine the relation between BCL11B and arterial function.
METHODS AND RESULTS: Here we report that BCL11B is expressed in the vascular smooth muscle where it regulates vascular stiffness. RNA sequencing of aortas from wild-type and Bcl11b null mice (BSMKO) identified the cGMP (cyclic guanosine monophosphate)-cGMP-dependent protein kinase G (PKG) as the most significant differentially regulated signaling pathway in BSMKO compared with wild-type mice. BSMKO aortas showed decreased levels of PKG1, increased levels of Ca++-calmodulin-dependent serine/threonine phosphatase calcineurin (PP2B) and decreased levels of their common phosphorylation target, phosphorylated vasodilator-stimulated phosphoprotein (pVASPS239), a regulator of cytoskelatal actin rearrangements. Decreased pVASPS239 in BSMKO aortas was associated with increased actin polymerization (filamentous/globular actin ratio). Functionally, aortic force, stress, wall tension, and stiffness, measured ex vivo in organ baths, were increased in BSMKO aortas, and BSMKO mice had increased pulse wave velocity, the in vivo index of arterial stiffness. Despite having no effect on blood pressure or microalbuminuria, increased arterial stiffness in BSMKO mice was associated with increased incidence of cerebral microbleeds compared with age-matched wild-type littermates.
CONCLUSIONS: We have identified vascular smooth muscle BCL11B as a crucial regulator of aortic smooth muscle function and a potential therapeutic target for vascular stiffness.
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License
© 2021 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.