Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening
| Autor: | Siqi Tan, Sebastian F. Barreto-Ortiz, Robert N. Cole, Huilei Wang, Dan E. Berkowitz, Tatiana Boronina, Marc K. Halushka, Sandeep Jandu, Lakshmi Santhanam, Marcel J. Rauer, Kavitha Nandakumar, Steven S. An, Wanqu Zhu, Yehudit Bergman, Jochen Steppan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Physiology Myocytes Smooth Muscle Aortic Diseases Lysyl oxidase Aorta Thoracic 030204 cardiovascular system & hematology Vascular Remodeling Nitric Oxide Muscle Smooth Vascular Protein-Lysine 6-Oxidase 03 medical and health sciences 0302 clinical medicine Vascular stiffness Vascular Stiffness Physiology (medical) Internal medicine Paracrine Communication medicine Animals Humans Pulse wave velocity Cells Cultured Mice Knockout Chemistry Age Factors Endothelial Cells musculoskeletal system Coculture Techniques Stiffening Extracellular Matrix 030104 developmental biology Endocrinology Vasoconstriction cardiovascular system Female Amino Acid Oxidoreductases Cardiology and Cardiovascular Medicine Signal Transduction circulatory and respiratory physiology Research Article |
| Zdroj: | Am J Physiol Heart Circ Physiol |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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