Relatively little is known regarding the cardiovascular pathology of HGPS. While there are cardiac and vascular commonalities between HGPS and aging, such as severe vessel blockage, there is also a lack of classical risk factors in HGPS such as hypercholesterolemia and increased serum hs-CRP,18
early stage hypertension, and smoking. Isolated from these risk factors, the study of HGPS may provide an opportunity to discover new elements that influence the vascular disease of aging. Reports to date have not examined genetically confirmed HGPS and therefore are difficult to interpret. Here we describe the cardiovascular pathology in two children with the de novo heterozygous mutation 1824C>T in LMNA
and typical HGPS disease course, who lack CVD risk factors established for the general population. In the face of this, we found global atherosclerosis and a pathologic profile that overlaps significantly with classic atherosclerosis of aging.
Similar to geriatric CVD, we found a spectrum of early to late-stage plaques in the HGPS patient samples. Arterial lesions in both typical atherosclerosis and HGPS exhibit calcification, inflammation, and evidence of plaque erosion and/or rupture. Although HGPS lesions tended to have smaller atheromatous cores relative to more typical atherosclerosis, this may be attributable to the lack of hypercholesterolemia and dyslipidemia in the HGPS patients. In our study, the composition of the HGPS lesions indicates that the ECM is similar to adult CVD consistent with progressive atherosclerotic lesion development and an in situ
Most likely, multiple cell types are involved in the HGPS vascular pathology. Macrophages may have a role as well as VSMC with their limited capacity for cell renewal.
In contrast to typical adult CVD however, we identified markedly thickened adventitia in large, medium and small arteries, and in veins. This is a new finding, not noted in previous reports of progeria cases. It would be anticipated that such profound fibrosis would lead to diminished vascular compliance, increased vessel stiffness and potential predisposition to formation of intimal plaque. In HGPS, progerin accumulation may be a major factor that underlies the development of these premature vascular lesions.
The adventitia is rapidly gaining recognition as an active participant in the development of atherosclerosis and vascular response to injuries. Aortic stiffness can contribute to increased afterload and development of left ventricular hypertrophy, such as that observed in patient HG001. Progressive vascular stiffness occurs in geriatric patients and is considered a major predictor of adverse coronary events,20
though it is typically accompanied by a much milder degree of adventitial fibrosis.
What underlies increased adventitial fibrosis observed in HGPS? Changes in collagen deposition and organization in response to mechanical stress or inflammation can result in adventitial fibrosis and luminal narrowing.21
In vitro, HGPS fibroblasts have decreased viability, are susceptible to oxidative stress and the nuclear lamina has a significantly reduced ability to rearrange under mechanical stress.22, 23, 24
Chronic ischemia can also induce adventitial fibrosis.25
These same factors play a role in the evolution of atherosclerosis of aging.26
Clinically, scleroderma-like skin findings and joint contractures in HGPS strongly imply that ECM abnormality is responsible for some disease sequellae. Further elucidation of the mechanisms that result in systemic vascular fibrosis in HGPS will aid more specifically targeted therapeutic interventions for this aspect of the disease. Given the abundance of dense collagen in the adventitia of the large and small arteries, it would be interesting to evaluate treatments that influence matrix architecture and tissue fibrosis, such as alagebrium27
or statins, 28, 29
For the first time, we show that progerin is widely present in the arterial walls and intimal plaques of HGPS patients; involving coronary arteries, aorta, arterioles and veins. VSMCs and adventitia showed dramatic accumulation of progerin localized into a thick rim-like structure at the nuclear envelope. Ubiquitous progerin presence within the vasculature implies a direct role for this protein, as well as possibly indirect influence, on progressive cardiovascular disease.
We also identify a new component in the typical aging process by demonstrating that progerin is present in the coronary arteries of non-HGPS aging individuals, and increases with advancing age. Thus, resident vascular cells infrequently use the cryptic splice site in exon 11 of LMNA in vivo
. Interestingly, in normal fibroblast lines, progerin-positive cells exhibit mitotic defects that increase with passage number.7, 8
This observation supports a correlation between progerin-induced mitotic abnormalities and normal aging. The highest number of progerin-positive cells in non-HGPS arteries was in the adventitia, introducing the possibility that some vessel insult is initiated in this deep vessel layer, and subsequently damages the intima, heralding plaque formation.
In our aging cohort, progerin-positive vascular cells were largely SMA negative. Although we did not attempt to further analyze their specific identity, their general shape was fibroblastoid. Some cells may be adventitial fibroblasts, or perhaps immune cells such as macrophages or other cell types that accumulate in response to resident cell death. Cells within the media could potentially be inflammatory cells as well, or SMA negative dedifferentiated VSMCs commonly found in atherosclerotic lesions.30
Future study to identify the progerin-positive cell types in aging vessels would help to elucidate what roles they play in the development of atherosclerosis.
Though the rodent model shows prominent SMC dropout from the media of older HGPS arteries 12
, medial SMC dropout is not a prominent feature in our human study. In our study, we cannot distinguish the mild medial cell dropout in HGPS from the typical secondary effects of atherosclerosis. The reasons for the murine and human differences are unclear but it should be noted that even in the mouse model, SMC dropout is highly variable within the vascular tree and some areas did not display loss (F. Collins, personal communication). Thus, the available sampling from the HGPS human cases may not have encompassed the same areas of the aorta that showed severe drop-out in mice. Of note, a prior human autopsy (though not definitively HGPS due to lack of genetic analysis), noted unusual aortic medial SMC depletion, the extent of which varied from site to site.10
Alternatively, medial cell death may not influence human vascular pathogenesis as strongly in the human as in the HGPS mouse model.
Additional work, beyond the scope of the current study, would be valuable in further elucidating a pathologic association between progerin expression and the development of atherosclerosis in both HGPS and the general population. For example, does the comparatively small—but steadily increasing–level of progerin influence age-related atherosclerosis by inducing a low-level smoldering chronic injury? This might explain the differences in adventitial pathology between HGPS, where progerin is extensive, and aging, where progerin is low but persistently increasing. The question could be addressed by study of progerin expression in a larger cohort of non-HGPS individuals with well defined cardiovascular medical history (low vs high CVD risk).
We speculate that progerin accumulation in vascular cells causes nuclear defects and increased susceptibility to mechanical strain that in turn triggers some combination of cell death, and inflammatory response, resulting in atherosclerosis. Since oxidative stress-induced free radicals have been implicated in vitro
in the pathology of HGPS 31 24
, a systematic quantitative comparison of lipid peroxidation products in HGPS and geriatric samples is warranted. Finally, because over-expression of farnesylated prelamin A has been implicated in progeroid damage 32, 33
, a systematic pathological examination of prelamin A expression in HGPS and in aging vessels could further identify key roles for altered lamin A proteins in these populations.
Atherosclerosis is a consequence of arterial wall healing in response to injury. In most individuals, this is a multifactorial process with contributions from a host of known risk factors (e.g., hypertension, hypercholesterolemia, etc.), but with a significant component of unidentified contributing factors. This study supports the possibility that progerin is a contributor to risk of atherosclerosis in the general population. The current observations arise from a small scale survey; however the presence of progerin in aging vasculature merits examination as a potential new element influencing vascular health with aging.