Core Concepts
Lysyl oxidase (LOX) plays a critical cell-autonomous role in regulating vascular smooth muscle cell cytoskeletal organization and contractility, in addition to its well-established extracellular matrix-modifying functions. Disruption of LOX leads to abnormal cytoskeletal dynamics, deregulated myosin light chain phosphorylation, and impaired calcium homeostasis, which together contribute to aortic aneurysm formation.
Abstract
The study investigates the mechanisms by which lysyl oxidase (LOX), a key extracellular matrix (ECM) modifying enzyme, contributes to the development of thoracic aortic disease (TAD) and aneurysms.
Key findings:
- Conditional deletion of Lox in vascular smooth muscle cells (VSMCs) leads to aneurysm formation in the aorta, even in the absence of hypertension. This suggests LOX plays critical intracellular roles beyond its ECM-modifying functions.
- LOX knockdown in human aortic smooth muscle cells (HAOSMCs) results in smaller cell size, disrupted cytoskeletal organization, and abnormal nuclear morphology - phenotypes that are independent of LOX's enzymatic activity.
- Mechanistically, LOX associates with cytoskeletal proteins and regulates the localization and organization of actin-binding proteins like Smoothelin, Myosin IIB, Calponin, and Transgelin. This leads to deregulation of myosin light chain (MLC) phosphorylation.
- LOX depletion also impairs calcium homeostasis in HAOSMCs, resulting in prolonged activation of the calcium-dependent MLC kinase (MLCK). This, along with the reduced expression of the Rho-associated kinases ROCK1/2, contributes to the irregular VSMC contraction observed in Lox-deficient aortas.
- The study highlights a previously unappreciated intracellular role for LOX in coordinating cytoskeletal organization, cell contraction, and ECM development - processes that are all critical for maintaining aortic wall integrity and preventing aneurysm formation.
Stats
Lox deletion in vascular smooth muscle cells leads to aneurysm formation in 100% of mice under hypertensive conditions, compared to only 11% in control mice.
Lox knockdown in human aortic smooth muscle cells results in a significant reduction in cell size.
Lox-depleted cells exhibit a 3.5-fold increase in the percentage of cells with irregular nuclear morphology compared to control cells.
The rate of calcium clearance from the cytoplasm is significantly inhibited in Lox knockdown cells compared to control cells.
Quotes
"Surprisingly, although LOX is one of the most prominent genes linked with TAD, no direct genetic assessment of its role specifically in VSMC has been carried out in vivo."
"Our results therefore highlight a missing link between the three distinct gene groups associated with aneurysms, thus serving as a molecular paradigm for the development of phenotypes that culminate in aneurysm."
"Altogether, the combined results suggest the observed LOX-dependent phenotypes, which cannot be compensated by exogenous LOX, are cell autonomous, and regulate the cells' ability to sense and respond to distinct ECM environments."