Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening

Jochen Steppan, Huilei Wang, Yehudit Bergman, Marcel J. Rauer, Siqi Tan, Sandeep Jandu, Kavitha Nandakumar, Sebastian Barreto-Ortiz, Robert N Cole, Tatiana N. Boronina, Wanqu Zhu, Marc K Halushka, Steven An, Dan E. Berkowitz, Lakshmi Santhanam

Research output: Contribution to journalArticle

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)H49-H59
JournalAmerican journal of physiology. Heart and circulatory physiology
Volume317
Issue number1
DOIs
StatePublished - Jul 1 2019

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Protein-Lysine 6-Oxidase
Blood Vessels
Smooth Muscle Myocytes
Pulse Wave Analysis
Vascular Stiffness
Vascular Smooth Muscle
Proteomics
Extracellular Matrix
Longitudinal Studies
Aorta
Molecular Biology
Nitric Oxide

Keywords

  • aging
  • lysyl oxidase-like 2
  • pulse-wave velocity
  • vascular stiffness

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening. / Steppan, Jochen; Wang, Huilei; Bergman, Yehudit; Rauer, Marcel J.; Tan, Siqi; Jandu, Sandeep; Nandakumar, Kavitha; Barreto-Ortiz, Sebastian; Cole, Robert N; Boronina, Tatiana N.; Zhu, Wanqu; Halushka, Marc K; An, Steven; Berkowitz, Dan E.; Santhanam, Lakshmi.

In: American journal of physiology. Heart and circulatory physiology, Vol. 317, No. 1, 01.07.2019, p. H49-H59.

Research output: Contribution to journalArticle

Steppan, Jochen ; Wang, Huilei ; Bergman, Yehudit ; Rauer, Marcel J. ; Tan, Siqi ; Jandu, Sandeep ; Nandakumar, Kavitha ; Barreto-Ortiz, Sebastian ; Cole, Robert N ; Boronina, Tatiana N. ; Zhu, Wanqu ; Halushka, Marc K ; An, Steven ; Berkowitz, Dan E. ; Santhanam, Lakshmi. / Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening. In: American journal of physiology. Heart and circulatory physiology. 2019 ; Vol. 317, No. 1. pp. H49-H59.
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AU - Tan, Siqi

AU - Jandu, Sandeep

AU - Nandakumar, Kavitha

AU - Barreto-Ortiz, Sebastian

AU - Cole, Robert N

AU - Boronina, Tatiana N.

AU - Zhu, Wanqu

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AU - Berkowitz, Dan E.

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AB - 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 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.

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