Chronic proteasome inhibition contributes to coronary atherosclerosis

Joerg Herrmann, Ardan M. Saguner, Daniele Versari, Timothy E. Peterson, Alejandro Chade, Monica Olson, Lilach O Lerman, Amir Lerman

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

The proteasome is responsible for the degradation of oxidized proteins, and proteasome inhibition has been shown to generate oxidative stress in vitro. Atherosclerosis is thought to be initiated as a consequence of increased endogenous oxidative stress. The current study was designed to assess whether chronic proteasome inhibition is associated with early coronary atherosclerosis. Female pigs, 3 months of age, were randomized to a normal (N) or high-cholesterol (HC) diet (2% cholesterol, 15% lard) without or with twice weekly subcutaneous injections of the proteasome inhibitor (PSI) MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary vasorelaxation to bradykinin (10 to 10- mol/L) and sodium nitroprusside (10 to 10 mol/L) was assessed by in vitro organ chamber experiments, intima-media ratio by morphometric analysis of Elastica-van Gieson-stained slides, and intima superoxide production by dihydroethidium fluorescence. Vasorelaxation to 10 mol/L bradykinin was reduced in HC compared with N (69±7 versus 90±2%, P<0.05) and further reduced in N+PSI and HC+PSI (57±6 and 48±13%, P<0.05 versus N and HC for each). Compared with N (0.03±0.01), intima-media ratio was higher in N+PSI (0.09±0.04, P<0.01) and HC+PSI (0.15±0.06, P<0.05). Compared with N (0.6±0.9% of intima area), dihydroethidium fluorescence was higher in HC, N+PSI, and HC+PSI (8.9±1.6, 6.0±3.5, and 7.2±3.9% of intima area, P<0.05 for all). Thus, chronic proteasome inhibition is associated with increased coronary artery oxidative stress and early atherosclerosis. These findings support the significance of the proteasome and related protein quality control for vascular biology and pathology.

Original languageEnglish (US)
Pages (from-to)865-874
Number of pages10
JournalCirculation Research
Volume101
Issue number9
DOIs
StatePublished - Oct 2007

Fingerprint

Proteasome Inhibitors
Proteasome Endopeptidase Complex
Coronary Artery Disease
Anticholesteremic Agents
Cholesterol
Oxidative Stress
Bradykinin
Vasodilation
Atherosclerosis
Fluorescence
Rubber
Nitroprusside
Subcutaneous Injections
Superoxides
Quality Control
Proteolysis
Blood Vessels
Coronary Vessels
Swine
Pathology

Keywords

  • Atherosclerosis
  • Endothelial dysfunction
  • Oxidative stress
  • Proteasome
  • Ubiquitin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Chronic proteasome inhibition contributes to coronary atherosclerosis. / Herrmann, Joerg; Saguner, Ardan M.; Versari, Daniele; Peterson, Timothy E.; Chade, Alejandro; Olson, Monica; Lerman, Lilach O; Lerman, Amir.

In: Circulation Research, Vol. 101, No. 9, 10.2007, p. 865-874.

Research output: Contribution to journalArticle

Herrmann, Joerg ; Saguner, Ardan M. ; Versari, Daniele ; Peterson, Timothy E. ; Chade, Alejandro ; Olson, Monica ; Lerman, Lilach O ; Lerman, Amir. / Chronic proteasome inhibition contributes to coronary atherosclerosis. In: Circulation Research. 2007 ; Vol. 101, No. 9. pp. 865-874.
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abstract = "The proteasome is responsible for the degradation of oxidized proteins, and proteasome inhibition has been shown to generate oxidative stress in vitro. Atherosclerosis is thought to be initiated as a consequence of increased endogenous oxidative stress. The current study was designed to assess whether chronic proteasome inhibition is associated with early coronary atherosclerosis. Female pigs, 3 months of age, were randomized to a normal (N) or high-cholesterol (HC) diet (2{\%} cholesterol, 15{\%} lard) without or with twice weekly subcutaneous injections of the proteasome inhibitor (PSI) MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary vasorelaxation to bradykinin (10 to 10- mol/L) and sodium nitroprusside (10 to 10 mol/L) was assessed by in vitro organ chamber experiments, intima-media ratio by morphometric analysis of Elastica-van Gieson-stained slides, and intima superoxide production by dihydroethidium fluorescence. Vasorelaxation to 10 mol/L bradykinin was reduced in HC compared with N (69±7 versus 90±2{\%}, P<0.05) and further reduced in N+PSI and HC+PSI (57±6 and 48±13{\%}, P<0.05 versus N and HC for each). Compared with N (0.03±0.01), intima-media ratio was higher in N+PSI (0.09±0.04, P<0.01) and HC+PSI (0.15±0.06, P<0.05). Compared with N (0.6±0.9{\%} of intima area), dihydroethidium fluorescence was higher in HC, N+PSI, and HC+PSI (8.9±1.6, 6.0±3.5, and 7.2±3.9{\%} of intima area, P<0.05 for all). Thus, chronic proteasome inhibition is associated with increased coronary artery oxidative stress and early atherosclerosis. These findings support the significance of the proteasome and related protein quality control for vascular biology and pathology.",
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