THE ROLES OF NUCLEAR LAMIN AND PROGERIN IN ENDOTHELIAL REMODELING AND WOUND HEALING RESPONSES UNDER FLUID SHEAR STRESS

As aging proceeds, the occurrence of cardiovascular diseases increases independent of other risk factors. At atherosclerotic sites, the rise in the senescent cell population was also observed. Patients with Hutchinson Gilford Progeria Syndrome (HGPS) also showed accelerated aging syndromes and extensive atherosclerosis progression, which was due to missense mutations on the LMNA gene that led to the production of progerin, an aberrant lamin A isoform instead of regular lamin A protein. Lamins act as structural and functional components in nuclear lamina, and recent findings suggested that the ectopic expression of mutant lamin A or lamin A precursor (prelamin A) not only caused defects in cell mechanics but also disturbed mechanotransduction pathways involving lamin A, both of which may contribute to vascular dysregulation. Moreover, the observation of the accumulation of prelamin A in normal aged vascular cells further suggests shared dysregulations involving lamin A in the vascular system between aged people and HGPS patients. In the vascular system, endothelial cells were well regulated by hemodynamic forces in vivo to maintain vascular homeostasis. Endothelial dysfunction, including impaired vasodilation and increased permeability, was regarded as the initial marker of atherosclerosis. Despite recent advancements and discussions about the potential mechanisms of progerin-induced vascular disorders, how progerin triggers endothelial dysfunction in a mechanical environment as an early event during atherosclerotic lesion formation has not been studied intensively. To help answer the gap question, we first set our goal to understand the effect of laminar flow at arterial levels on endothelial lamins as part of the aging process. Spatial and temporal changes in lamin A/C expression were observed as cell passage went up without flow present. As shear stress was applied, lamin A/C expressions were modulated on both transcriptional and translational levels, which were also dependent on PDL. To further examine how ...