Nuclear factor {kappa}B-mediated transactivation of telomerase prevents intimal smooth muscle cell from replicative senescence during vascular repair

• OBJECTIVE: To gain insights into mechanisms by which intimal hyperplasia interferes with the repair process by investigating expression and function of the catalytic telomerase reverse transcriptase (TERT) subunit after vascular injury. METHODS AND RESULTS: Functional telomerase is essential to the replicative longevity of vascular cells. We found that TERT was de novo activated in the intima of injured arteries, involving activation of the nuclear factor kappaB pathway. Stimulation of the isolated intimal smooth muscle cell (SMC) by basic fibroblast growth factor or tumor necrosis factor alpha resulted in increased TERT activity. This depends on the activation of c-Myc signaling because mutation of the E-box in the promoter or overexpression of mitotic arrest deficient 1 (MAD1), a c-Myc competitor, abrogated the transcriptional activity. Inhibition of nuclear factor kappaB in both intimal SMCs and the injured artery attenuated TERT transcriptional activity through reduction of c-Myc expression. Pharmacological blockade of TERT led to SMC senescence. Finally, depletion of telomerase function in mice resulted in severe intimal SMC senescence after vascular injury. CONCLUSIONS: These results support a model in which vascular injury induces de novo expression of TERT in intimal SMCs via activation of nuclear factor kappaB and upregulation of c-Myc. The resumed TERT activity is critical for intimal hyperplasia.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

Aminobenzoic Acids/pharmacology

Animals

Binding Sites

Carotid Artery Injuries/*enzymology/genetics/pathology

*Cell Aging/drug effects

*Cell Proliferation/drug effects

Cells

Cultured

Disease Models

Animal

Enzyme Inhibitors/pharmacology

Fibroblast Growth Factor 2/metabolism

Gene Expression Regulation

Enzymologic

Hyperplasia

I-kappa B Kinase/genetics/metabolism

Male

Mice

Mice

Knockout

Myocytes

Smooth Muscle/drug effects/*enzymology/pathology

NF-kappa B/*metabolism

Naphthalenes/pharmacology

Promoter Regions

Genetic

Proto-Oncogene Proteins c-myc/metabolism

RNA/genetics

RNA

Messenger/metabolism

Rats

Rats

Sprague-Dawley

Telomerase/antagonists & inhibitors/deficiency/genetics/*metabolism

*Transcriptional Activation

Transduction

Genetic

Tumor Necrosis Factor-alpha/metabolism

Tunica Intima/drug effects/*enzymology/pathology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)