Mechanisms Of Early Arterial Stiffening And Reduced Smooth Muscle Contractility In The Premature Aging Disease Hutchinson-Gilford Progeria Syndrome

Ryan Von Kleeck, University of Pennsylvania

Abstract

Hutchinson-Gilford Progeria syndrome (HGPS) is a rare premature aging disease in which children present with a rapid onset of clinical characteristics of aging. Ultimately, HGPS children die in their teen years due to severe cardiovascular disease leading to heart attack and stroke. Despite discovering the mutation resulting in HGPS, a single nucleotide point mutation in the Lamin A gene, how this mutated form of Lamin A, termed progerin, results in such severe cardiovascular pathology is not well understood. Although HGPS children do not have altered blood lipid profiles, they present with increased arterial stiffness, a cholesterol-independent risk factor for cardiovascular disease that is also increased in the normal aging population. Toward the end of their lifespan, the arteries of HGPS patients display a dramatic loss of smooth muscle cells (SMCs) and a highly collagenous, fibrotic environment. However, the initial driving factors of arterial stiffening and the decline in smooth muscle cell function are not well characterized. In this work, I use the LMNAG609G/G609G mouse model (hereafter referred to as HGPS mice), which harbors the equivalent mutation to that seen in the human disease, to study causal factors initiating arterial stiffening and SMC decline in young mice. I found that the onset of arterial stiffening in HGPS mice highly correlates with an increase in the collagen cross linking enzyme Lysyl Oxidase (LOX), and pharmacologic inhibition of LOX in vivo corrected arterial stiffening and heart defects, such as diastolic dysfunction, present in HGPS mice. Interestingly, I found that normally aged mouse arteries also present with arterial stiffening and increased LOX abundance, although distinct from that seen in HGPS. Furthermore, I found that SMC function declines well before the loss of SMCs from HGPS mouse arteries, as young HGPS mice presented with decreased arterial contractility at an early age. I correlated this decrease in arterial contractility with a reduction in smooth muscle myosin heavy chain (SM-MHC), and restoration of SM-MHC corrected the decreased force generation exhibited by isolated HGPS SMCs. Consistent with observations in HGPS mice, aged mouse arteries also presented with decreased contractility and SM-MHC, although whether the mechanisms are similar or distinct from that of HGPS requires further study. Overall, these studies demonstrate that arterial stiffening and decline in SMC function occur at a very early age in HGPS and replicate many of the phenotypes seen in normal aged arteries. Insight from this study provides new understanding of the early driving factors of arterial stiffening and decline in SMC function and sheds light on potential therapeutic approaches to reduce the burden of cardiovascular disease in HGPS.