58
cerebrovascular arteries, eventually leading to fatal myocardial infarction or stroke
at a mean age of 13 years old [67]. Classical HGPS is caused by a “de novo” point
mutation in the LMNA gene, leading to the production of an aberrant protein named
progerin [36]. Progerin accumulates in the nuclear membrane, prompting nuclear
morphology abnormalities, misregulated gene expression, loss of peripheral heterochromatin, mitochondrial dysfunction, defects in DNA repair, alternate splicing,
epigenetic changes, accelerated telomere shortening, and premature senescence
[44]. The same molecular mechanisms occur during normal aging, supporting the
notion that HGPS mimics at least some aspects of physiological aging (Fig. 3.1).
This can be partially explained by the fact that levels of progerin increase during
physiological aging, although not at a same degree as in HGPS-affected cells [103].
Although not all features of physiological aging are manifested in this syndrome,
from a cardiovascular standpoint, the case reports seem to be very consistent with a
premature aging phenotype [7]. In fact, it has been shown that progerin accumulates
mainly in the nucleus of vascular cells such as ECs, SMCs, and fibroblasts. It has
also been shown that progerin is widely present in the arterial walls and intimal
arteriosclerotic plaques of HGPS patients, similar to healthy aged individuals [74,
86]. This evidence partially explains the severity of the cardiovascular phenotype in
HGPS children. Development of advanced fibrotic arteriosclerosis with calcification and overall thickening and stiffening of the arterial walls, as well as mild systemic inflammation levels, are some of the HGPS vascular symptoms that also
typically occur in normal aging [86].
3.4.1 Altered ECM Remodeling
HGPS patients show vessel walls with marked fibrosis, having high stiffness and a
decreased compliance of the vessels. Autopsies of HGPS patients reveal an accumulation of type I and type IV collagen and of proteoglycans, such as decorin and
versican, as well as deposition of hyaluron in the arteriosclerotic lesions [86].
Genome-scale expression profiling of HGPS and aged-donor fibroblasts have shown
altered expression of genes involved in ECM synthesis or modification [28, 68].
There is an upregulation of proteoglycan cell adhesion proteins, which are important for ECM stability and for binding other proteoglycans, hyaluron, and fibrous
matrix proteins such as collagen [28, 68]. Laminin, a protein that forms essential
interactions with collagen type IV and associates with cell-binding proteins, is also
upregulated, thereby influencing cell attachment, morphology, and survival. A
mouse model of HGPS showed increased arterial hyaluron content with age [126].
Hyaluron is an important ECM component, highly related to SMC proliferation and
migration, and has been demonstrated to accumulate in early arteriosclerosis. The
increased expression of fibrous proteins of the ECM, including collagen fibers, contributes to a decline in vessel elasticity [28, 68].
The ECM remodeling profile in HGPS is affected by enzyme expression. Studies
have shown a specific downregulation of MMP-3 expression in HGPS cell lines and
P. R. Pitrez et al.
cerebrovascular arteries, eventually leading to fatal myocardial infarction or stroke
at a mean age of 13 years old [67]. Classical HGPS is caused by a “de novo” point
mutation in the LMNA gene, leading to the production of an aberrant protein named
progerin [36]. Progerin accumulates in the nuclear membrane, prompting nuclear
morphology abnormalities, misregulated gene expression, loss of peripheral heterochromatin, mitochondrial dysfunction, defects in DNA repair, alternate splicing,
epigenetic changes, accelerated telomere shortening, and premature senescence
[44]. The same molecular mechanisms occur during normal aging, supporting the
notion that HGPS mimics at least some aspects of physiological aging (Fig. 3.1).
This can be partially explained by the fact that levels of progerin increase during
physiological aging, although not at a same degree as in HGPS-affected cells [103].
Although not all features of physiological aging are manifested in this syndrome,
from a cardiovascular standpoint, the case reports seem to be very consistent with a
premature aging phenotype [7]. In fact, it has been shown that progerin accumulates
mainly in the nucleus of vascular cells such as ECs, SMCs, and fibroblasts. It has
also been shown that progerin is widely present in the arterial walls and intimal
arteriosclerotic plaques of HGPS patients, similar to healthy aged individuals [74,
86]. This evidence partially explains the severity of the cardiovascular phenotype in
HGPS children. Development of advanced fibrotic arteriosclerosis with calcification and overall thickening and stiffening of the arterial walls, as well as mild systemic inflammation levels, are some of the HGPS vascular symptoms that also
typically occur in normal aging [86].
3.4.1 Altered ECM Remodeling
HGPS patients show vessel walls with marked fibrosis, having high stiffness and a
decreased compliance of the vessels. Autopsies of HGPS patients reveal an accumulation of type I and type IV collagen and of proteoglycans, such as decorin and
versican, as well as deposition of hyaluron in the arteriosclerotic lesions [86].
Genome-scale expression profiling of HGPS and aged-donor fibroblasts have shown
altered expression of genes involved in ECM synthesis or modification [28, 68].
There is an upregulation of proteoglycan cell adhesion proteins, which are important for ECM stability and for binding other proteoglycans, hyaluron, and fibrous
matrix proteins such as collagen [28, 68]. Laminin, a protein that forms essential
interactions with collagen type IV and associates with cell-binding proteins, is also
upregulated, thereby influencing cell attachment, morphology, and survival. A
mouse model of HGPS showed increased arterial hyaluron content with age [126].
Hyaluron is an important ECM component, highly related to SMC proliferation and
migration, and has been demonstrated to accumulate in early arteriosclerosis. The
increased expression of fibrous proteins of the ECM, including collagen fibers, contributes to a decline in vessel elasticity [28, 68].
The ECM remodeling profile in HGPS is affected by enzyme expression. Studies
have shown a specific downregulation of MMP-3 expression in HGPS cell lines and
P. R. Pitrez et al.