Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome

Hamczyk, Magda R.; Campo, Lara del; Andrés, Vicente

doi:10.1146/annurev-physiol-021317-121454

Cited by 88 publications

(90 citation statements)

References 143 publications

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“…For HGPS patients, whose cardiovascular system is particularly affected, this includes two of the heart's fundamental components: vascular smooth muscle cells and cardiomyocytes (Anversa & Nadal‐Ginard, ; Bergmann et al, , ). In addition, the importance of cycling cell types in progeria is underscored by a recent report showing that progerin expression restricted to vascular smooth muscle cells recapitulates many of the HGPS‐associated cardiovascular defects (Hamczyk, Campo, & Andrés, ). Lastly, we provide evidence that heterochromatin levels are rapidly restored upon progerin removal and that transient exposure to progerin in G1‐arrested cells does not result in any lasting proliferative defect.…”

Section: Discussionmentioning

confidence: 99%

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

et al. 2020

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Hutchinson–Gilford progeria is a premature aging syndrome caused by a truncated form of lamin A called progerin. Progerin expression results in a variety of cellular defects including heterochromatin loss, DNA damage, impaired proliferation and premature senescence. It remains unclear how these different progerin‐induced phenotypes are temporally and mechanistically linked. To address these questions, we use a doxycycline‐inducible system to restrict progerin expression to different stages of the cell cycle. We find that progerin expression leads to rapid and widespread loss of heterochromatin in G1‐arrested cells, without causing DNA damage. In contrast, progerin triggers DNA damage exclusively during late stages of DNA replication, when heterochromatin is normally replicated, and preferentially in cells that have lost heterochromatin. Importantly, removal of progerin from G1‐arrested cells restores heterochromatin levels and results in no permanent proliferative impediment. Taken together, these results delineate the chain of events that starts with progerin expression and ultimately results in premature senescence. Moreover, they provide a proof of principle that removal of progerin from quiescent cells restores heterochromatin levels and their proliferative capacity to normal levels.

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Section: Discussionmentioning

confidence: 99%

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

et al. 2020

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“…Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare genetic disease characterized by accelerated aging and death in adolescence [5][6][7][8][9]. HGPS children have impaired postnatal growth, lipodystrophy, alopecia, pigmented and wrinkled skin, and skeletal dysplasia.…”

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confidence: 99%

“…Interestingly, "Lamin C-Stop" mice (LCS) expressing Lamin C but lacking lamin A are apparently normal, but are slightly heavier and longer-lived than wild-type controls [21]. Over the last decade, several animal models of HGPS have been generated and characterized [6,22]. Lmna G609G/G609G mice, which express ubiquously progerin and lamin C and lack lamin A, recapitulate the main clinical manifestations of human HGPS, such as difficulty to thrive, lipodystrophy, skeleton abnormalities, vascular calcification and stiffening, vascular smooth muscle cell (VSMC) loss, and premature death [23][24][25].…”

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confidence: 99%

Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment

Campo

Sánchez‐López

González‐Gómez

et al. 2020

Cells

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Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson-Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid Lmna G609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined Lmna LCS/LCS Tie2Cre tg/+ and Lmna LCS/LCS Sm22αCre tg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare genetic disease characterized by accelerated aging and death in adolescence [5][6][7][8][9]. HGPS children have impaired postnatal growth, lipodystrophy, alopecia, pigmented and wrinkled skin, and skeletal dysplasia. They also develop generalized atherosclerosis, arterial stiffness and calcification, electrocardiographic abnormalities, and ventricular diastolic dysfunction and die prematurely at an average age of 14.6 years mainly due to myocardial infarction, stroke, or heart failure [7,10,11]. HGPS is caused by a heterozygous de novo point mutation in the LMNA gene, which encodes the nuclear proteins lamin A and C (A-type lamins) [12,13]. This synonymous mutation activates a cryptic splice donor site that removes 150 nucleotides from exon 11, causing the synthesis of progerin [12,13]. This truncated form of prelamin A is expressed ubiquitously and acts in a dominant-negative manner, causing alterations in many essential nuclear functions, including nuclear structure, gene transcription, signal transduction, DNA damage repair, chromatin organization, mechanosensing, and proliferation [14,15]. Aside from its role in HGPS, progerin is detectable at low levels in several tissues during normal aging, including atherosclerotic coronary arteries, suggesting a role in physiological aging [11,[16][17][18][19].Homozygous Lmna-null mice lacking A-type lamins develop to term without exhibiting overt anomalies, but they develop skeletal muscle dystrophy and dilated cardiomyopathy soon after birth and are all death by the eight week [20]. Interest...

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“…HGPS is driven by a de novo mutation in the LMNA gene, which yields a farnesylated and truncated prelamin A protein, known as Progerin (Gonzalo, Kreienkamp, & Askjaer, 2017). Progerin accumulation disrupts the nuclear lamina integrity, causing miss‐shaped nuclei, loss of heterochromatin, abnormal epigenetics, and altered gene expression and defective DNA repair (Columbaro et al, 2005; Gonzalo et al, 2017; Hamczyk, del Campo, & Andres, 2018; Liu et al, 2005; Mattioli et al, 2018). Farnesylation is critical for HGPS pathogenesis as nonfarnesylated Progerin protein fails to accelerate aging in mouse models.…”

Section: Introductionmentioning

confidence: 99%

“…Farnesylation is critical for HGPS pathogenesis as nonfarnesylated Progerin protein fails to accelerate aging in mouse models. Nuclear defects in HGPS cells can be largely alleviated by farnesyltransferase inhibitors (FTIs) (Capell et al, 2005; Hamczyk et al, 2018; Toth et al, 2005). However, disruption to other nuclear compartments, such as nuclear bodies, in HGPS is rarely reported (Harhouri et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

Wang

Qian

et al. 2020

Aging Cell

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Progerin accumulation disrupts nuclear lamina integrity and causes nuclear structure abnormalities, leading to premature aging, that is, Hutchinson–Gilford progeria syndrome (HGPS). The roles of nuclear subcompartments, such as PML nuclear bodies (PML NBs), in HGPS pathogenesis, are unclear. Here, we show that classical dot‐like PML NBs are reorganized into thread‐like structures in HGPS patient fibroblasts and their presence is associated with late stage of senescence. By co‐immunoprecipitation analysis, we show that farnesylated Progerin interacts with human PML2, which accounts for the formation of thread‐like PML NBs. Specifically, human PML2 but not PML1 overexpression in HGPS cells promotes PML thread development and accelerates senescence. Further immunofluorescence microscopy, immuno‐TRAP, and deep sequencing data suggest that these irregular PML NBs might promote senescence by perturbing NB‐associated DNA repair and gene expression in HGPS cells. These data identify irregular structures of PML NBs in senescent HGPS cells and support that the thread‐like PML NBs might be a novel, morphological, and functional biomarker of late senescence.

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Aging in the Cardiovascular System: Lessons from Hutchinson-Gilford Progeria Syndrome

Cited by 88 publications

References 143 publications

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

Heterochromatin loss as a determinant of progerin‐induced DNA damage in Hutchinson–Gilford Progeria

Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment

PML2‐mediated thread‐like nuclear bodies mark late senescence in Hutchinson–Gilford progeria syndrome

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