Lysyl oxidase-like 2 (LOXL2) depletion is protective in age-associated vascular stiffening.

Authors:
Jochen Steppan
Jochen Steppan
Johns Hopkins University
Baltimore | United States
Sandeep Jandu
Sandeep Jandu
Johns Hopkins University
Ellicott City | United States
Robert N Cole
Robert N Cole
Johns Hopkins University School of Medicine
Baltimore | United States

Am J Physiol Heart Circ Physiol 2019 Apr 19. Epub 2019 Apr 19.

ACCM, Johns Hopkins University, United States.

Vascular stiffening and its sequelae are major causes of morbidity and mortality in the elderly. The increasingly accepted concept of "smooth muscle cell (SMC) stiffness syndrome" along with matrix deposition has emerged in vascular biology to account for the mechanical phenotype of arterial aging, but the molecular targets remain elusive. In this study, using an unbiased proteomic analysis, we identified lysyl oxidase-like 2 (LOXL2) as a critical SMC mediator for age-associated vascular stiffening. We tested the hypothesis that loss of LOXL2 function is protective in aging-associated vascular stiffening. We determined that exogenous and endogenous NO markedly decreased LOXL2 abundance and activity in the extracellular matrix of isolated SMCs, and LOXL2 endothelial cells suppress LOXL2 abundance in the aorta. In a longitudinal study, LOXL2+/- mice were protected from age-associated increase in pulse wave velocity, an index of vascular stiffening, as occurred in littermate wild-type (WT) mice. Using isolated aortic segments, we found that LOXL2 mediates vascular stiffening in aging by promoting SMC stiffness, augmented SMC contractility, and vascular matrix deposition. Together, these studies establish LOXL2 as a nodal point for a new therapeutic approach to treat age-associated vascular stiffening.

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Source
https://www.physiology.org/doi/10.1152/ajpheart.00670.2018
Publisher Site
http://dx.doi.org/10.1152/ajpheart.00670.2018DOI Listing
April 2019
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