X-Message-Number: 23781
Date: Tue, 30 Mar 2004 21:03:23 -0800 (PST)
From: Doug Skrecky <>
Subject: rosuvastatin may rejuvenate arteries

Circulation. 2003 Jul 29;108(4):457-63. Epub 2003 Jul 14
Aging, progenitor cell exhaustion, and atherosclerosis.

  BACKGROUND: Atherosclerosis is largely attributed to chronic vascular
injury, as occurs with excess cholesterol; however, the effect of
concomitant vascular aging remains unexplained. We hypothesize that the
effect of time in atherosclerosis progression is related to obsolescence
of endogenous progenitor cells that normally repair and rejuvenate the
arteries. METHODS AND RESULTS: Here we show that chronic treatment with
bone marrow-derived progenitor cells from young nonatherosclerotic
ApoE-/- mice prevents atherosclerosis progression in ApoE-/- recipients
despite persistent hypercholesterolemia. In contrast, treatment with bone
marrow cells from older ApoE-/- mice with atherosclerosis is much less
effective. Cells with vascular progenitor potential are decreased in the
bone marrow of aging ApoE-/- mice, but cells injected from donor mice
engraft on recipient arteries in areas at risk for atherosclerotic injury.
CONCLUSIONS: Our data indicate that progressive progenitor cell deficits
may contribute to the development of atherosclerosis.

Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1567-72.
Bone marrow-derived progenitor cells modulate vascular
reendothelialization and neointimal formation: effect of
3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition.

  OBJECTIVE: Atherosclerosis and restenosis after vascular injury are both
characterized by endothelial dysfunction, apoptosis, inappropriate
endothelialization, and neointimal formation. Bone marrow-derived
endothelial progenitor cells have been implicated in neovascularization,
resulting in adult blood vessel formation. Despite the anticipated stem
cell plasticity, the role of bone marrow-derived endothelial progenitor
cells has not been clarified in vascular lesion development. METHODS AND
RESULTS: We investigated vascular lesion formation in mice after
transplantation of bone marrow transfected by means of retrovirus with
enhanced green fluorescent protein. Carotid artery injury was induced,
resulting in neointimal formation. Fluorescence microscopy and
immunohistological analysis revealed that bone marrow-derived progenitor
cells are involved in reendothelialization of the
vascular lesions. Treatment with rosuvastatin (20 mg/kg body wt per day),
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, enhanced the
circulating pool of endothelial progenitor cells, propagated the advent
of bone marrow-derived endothelial cells in the injured vessel wall, and,
thereby, accelerated reendothelialization and significantly decreased
neointimal formation. CONCLUSIONS: Vascular lesion development initiated
by endothelial cell damage is moderated by bone marrow-derived progenitor
cells. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibition
promotes bone marrow-dependent reendothelialization and diminishes
vascular lesion development. These findings may help to establish novel
pathophysiological concepts and therapeutic strategies in the treatment
of various cardiovascular diseases.

J Clin Invest. 2004 Jan;113(2):175-9.
Bmi1, stem cells, and senescence regulation.

  Stem cells generate the differentiated cell types within many organs
throughout the lifespan of an organism and are thus ultimately
responsible for the longevity of multicellular organisms. Therefore,
senescence of stem cells must be prevented. Bmi1 is required for the
maintenance of adult stem cells in some tissues partly because it
represses genes that induce cellular senescence and cell death.

J Clin Invest. 2004 Jan;113(2):160-8
Telomeres, stem cells, senescence, and cancer.

  Mammalian aging occurs in part because of a decline in the restorative
capacity of tissue stem cells. These self-renewing cells are rendered
malignant by a small number of oncogenic mutations, and overlapping tumor
suppressor mechanisms (e.g., p16(INK4a)-Rb, ARF-p53, and the telomere)
have evolved to ward against this possibility. These beneficial antitumor
pathways, however, appear also to limit the stem cell life span, thereby
contributing to aging.

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