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Angiotensin II Induced Premature Senescence of Human Vascular Smooth Muscle Cells

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thesis
posted on 2011-07-21, 12:16 authored by Yogita Mistry
Senescence is a state of irreversible growth arrest in cells with potentially tumourigenic changes such as irreparable DNA damage. However, senescent cells accumulate with age, altering tissue structure and function and have been observed in atherosclerotic plaques and at sites predisposed to atheroma in man. Recent studies show that long term inhibition of the renin-angiotensin system attenuates the effects of ageing in rodent cardiovascular tissue. Therefore, this thesis investigated whether angiotensin II accelerates senescence of human vascular smooth muscle cells (hVSMC) in vitro and whether the mechanism involves reactive oxygen species, DNA damage, telomere attrition and cell cycle regulatory proteins. Since mitochondria are integral to theories of cellular ageing, the effect of angiotensin II on mitochondrial biogenesis and function were studied. Angiotensin II exposure enhanced superoxide generation via NADPH oxidase in hVSMC, although inhibitors identified the mitochondrial respiratory chain as a contributing source. Angiotensin II induced DNA stand breaks in the Comet assay and accelerated telomere attrition. Senescence associated-β-galactosidase activity was induced by angiotensin II after exposure for 30 days, but also after just 24 hours and after successive short treatments over three days. These effects were attenuated by an angiotensin II type-1 receptor antagonist and antioxidants. Simultaneously, increased expression of p21 and p53 were observed. Angiotensin II induced alterations in mitochondria. A rapid increase in mtDNA content, gene transcript levels involved in initiating mtDNA transcription and replication and ATP levels in hVSMC, suggested mitochondrial biogenesis occurs in response to stress. These data suggest that angiotensin II induces both accelerated replicative senescence (telomere-dependent) and stress-induced premature senescence (telomere-independent) of hVSMC, dependent upon the treatment regime used. These findings explain the anti-ageing effects of life-long angiotensin II blockade in rodents, and may provide a mechanism for accelerated vascular ageing and cardiovascular disease progression in the ageing human population.

History

Supervisor(s)

Herbert, Karl E.; Williams, Bryan

Date of award

2009-07-03

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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