TY - JOUR
T1 - Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening
AU - Steppan, Jochen
AU - Wang, Huilei
AU - Bergman, Yehudit
AU - Rauer, Marcel J.
AU - Tan, Siqi
AU - Jandu, Sandeep
AU - Nandakumar, Kavitha
AU - Barreto-Ortiz, Sebastian
AU - Cole, Robert N.
AU - Boronina, Tatiana N.
AU - Zhu, Wanqu
AU - Halushka, Marc K.
AU - An, Steven S.
AU - Berkowitz, Dan E.
AU - Santhanam, Lakshmi
N1 - Publisher Copyright:
© 2019 the American Physiological Society.
PY - 2019
Y1 - 2019
N2 - Vascu-lar 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 nitric oxide 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 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. NEW & NOTEWORTHY Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.
AB - Vascu-lar 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 nitric oxide 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 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. NEW & NOTEWORTHY Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.
KW - Aging
KW - Lysyl oxidase-like 2
KW - Pulse-wave velocity
KW - Vascular stiffness
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U2 - 10.1152/ajpheart.00670.2018
DO - 10.1152/ajpheart.00670.2018
M3 - Article
C2 - 31002285
AN - SCOPUS:85068488146
SN - 0363-6135
VL - 317
SP - H49-H59
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 1
ER -