Mechanisms of Premature Vascular Aging in Children With Hutchinson-Gilford Progeria Syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, segmental premature aging syndrome of accelerated atherosclerosis and early death from myocardial infarction or stroke. This study sought to establish comprehensive characterization of the fatal vasculopathy in HGPS and its relevance to normal aging. We performed cardiovascular assessments at a single clinical site on the largest prospectively studied cohort to date. Carotid-femoral pulse wave velocity was dramatically elevated (mean 13.00±3.83 m/s). Carotid duplex ultrasound echobrightness, assessed in predefined tissue sites as a measure of arterial wall density, was significantly greater than age- and gender-matched controls in the intima-media (P<0.02), near adventitia (P<0.003) and deep adventitia (P<0.01), as was internal carotid artery mean flow velocity (p<0.0001). Ankle-brachial indices were abnormal in 78% of patients. Effective disease treatments may be heralded by normalizing trends of these noninvasive cardiovascular measures. The data demonstrates that, along with peripheral vascular occlusive disease, accelerated vascular stiffening is an early and pervasive mechanism of vascular disease in HGPS. There is considerable overlap with cardiovascular changes of normal aging, which reinforces the view that defining mechanisms of cardiovascular disease in HGPS provides a unique opportunity to isolate a subset of factors influencing cardiovascular disease in the general aging population.

Prelamin A Accelerates Vascular Calcification Via Activation of the DNA Damage Response and Senescence-Associated Secretory Phenotype in Vascular Smooth Muscle Cells

“…Each isolate was carefully characterized with respect to proliferative capacity and passage number at senescence as described below. For most isolates senescence occurred at passages [15][16]. For all studies, excluding those were serial passaging to senescence was performed, early passage VSMCs within the proliferative phase of growth between passages 5 and 10 were used.…”

“…9 These modification steps are critical because the mutation carried by patients with HGPS prevents cleavage and thus lamin A maturation, resulting in the development of premature aging, including premature atherosclerosis/arteriosclerosis, characterized by VSMC degeneration and calcification, [10][11][12] and leading to vascular stiffness and myocardial infarction or stroke at an average age of 13 years. 8,[13][14][15][16] In both human and animal studies, prelamin A accumulation has been shown to occur selectively in the vasculature, and prelamin A-induced VSMC calcification and senescence are reiterated in animal models of HGPS and in vascular cells differentiated from induced pluripotent stem cells derived from patients with HGPS. [17][18][19][20] The mechanisms leading to premature aging and associated pathological changes are poorly understood; however, prelamin A has been shown to interfere with DNA damage repair signaling, leading to premature cell senescence.…”

Lamins at a glance

“…In contrast to lamin-deficient cells, cells from patients with HutchinsonGilford progeria syndrome (HGPS) develop increasingly stiffer nuclei (Dahl et al, 2006;Verstraeten et al, 2008), possibly as a result of accumulation of progerin at the nuclear envelope. Interestingly, HGPS cells and cells lacking A-type lamins are more susceptible to mechanically induced cell death (Lammerding et al, 2004;Verstraeten et al, 2008), providing a possible mechanism for the progressive loss of vascular smooth muscle cells in blood vessels and the arteriosclerotic disease in HGPS (Capell et al, 2007;Dahl et al, 2010;Gerhard-Herman et al, 2012Merideth et al, 2008Stehbens et al, 2001) and muscle loss in EDMD. In addition to affecting nuclear stability, loss of A-type lamins and mutations linked to EDMD can also disrupt nucleo-cytoskeletal coupling, resulting in the loss of synaptic nuclei from neuromuscular junctions (Méjat et al, 2009), impaired nuclear movement and positioning and disturbed cytoskeletal organization (reviewed by Méjat and Misteli, 2010).…”

Imaging Characteristics of Cerebrovascular Arteriopathy and Stroke in Hutchinson-Gilford Progeria Syndrome

“…Cardiovascular disease in HGPS has been characterized in several prospective cohort studies. 9,10 Postmortem studies have identified fatty plaques and complex calcified lesions within coronary arteries. 6,[11][12][13] Despite the prevalence of cerebrovascular disease in HGPS, little is known about the nature of strokes and vascular characteristics of the head and neck in these patients.…”

“…6,[11][12][13] Despite the prevalence of cerebrovascular disease in HGPS, little is known about the nature of strokes and vascular characteristics of the head and neck in these patients. Carotid sonography has identified atherosclerotic plaque in cervical arteries 9,10 and isolated case reports of ICA and VA stenoses and occlusions in children with HGPS have presumed atherosclerosis as the underlying etiology in the absence of histologic confirmation. The goal of this study was to determine the incidence, imaging characteristics, and natural history of cerebrovascular disease in a large cohort of children with HGPS and to compare these findings with the established characteristics of cerebrovascular disease in the aging non-HGPS population.…”