Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.
BACKGROUND
Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition.


RESULTS
To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs. In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects, and these defects were reversible by treatment with farnesylation inhibitors and statins. In human arteries, prelamin A accumulation was not observed in young healthy vessels but was prevalent in medial VSMCs from aged individuals and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. Prelamin A accumulation correlated with downregulation of the lamin A processing enzyme Zmpste24/FACE1, and FACE1 mRNA and protein levels were reduced in response to oxidative stress. Small interfering RNA knockdown of FACE1 reiterated the prelamin A-induced nuclear morphology defects characteristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence. We show that prelamin A acts to disrupt mitosis and induce DNA damage in VSMCs, leading to mitotic failure, genomic instability, and premature senescence.


CONCLUSIONS
This study shows that prelamin A is a novel biomarker of VSMC aging and disease that acts to accelerate senescence. It therefore represents a novel target to ameliorate the effects of age-induced vascular dysfunction.
Ragnauth
Cassandra D
CD
Division of Cardiovascular Medicine, Kings College London, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK.
Warren
Derek T
DT
Liu
Yiwen
Y
McNair
Rosamund
R
Tajsic
Tamara
T
Figg
Nichola
N
Shroff
Rukshana
R
Skepper
Jeremy
J
Shanahan
Catherine M
CM
D000375:Aging / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000648:ultrastructure; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage; D015536:Down-Regulation; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008938:Mitosis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011498:Protein Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D015415:Biomarkers; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; C090764:prelamin A; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human